Biomacromolecules 2005, 6, 489-497
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Structure-Property Relationships of Copolymers Obtained by Ring-Opening Polymerization of Glycolide and E-Caprolactone. Part 2. Influence of Composition and Chain Microstructure on the Hydrolytic Degradation Suming Li,*,† Piotr Dobrzynski,*,‡ Janusz Kasperczyk,‡ Maciej Bero,‡ Christian Braud,† and Michel Vert† Centre de Recherche sur les Biopolymeres Artificiels, Faculte de Pharmacie, 15 avenue Charles Flahault, BP 14492, 34093 Montpellier Cedex 05, France, and Centre of Polymer Chemistry, Polish Academy of Sciences, 41-808 Zabrze, Curie-Sklodowska 34 Poland Received September 3, 2004
A series of glycolide/-caprolactone copolymers were compression molded and allowed to degrade in a pH 7.4 phosphate buffer at 37 °C. Degradation was monitored by various analytical techniques such as 1H NMR, X-ray diffraction, DSC, CZE, ESI-MS, and inherent viscosity measurements. The results show that the degradation rate depends not only on the copolymer composition but also on its chain microstructure. Generally, copolymers with a higher C-G bond content or a higher degree of randomness exhibit higher degradation rates. Sequences with odd numbers of glycolyl units such as -CGC- and -CGGGC-, which result from the second mode transesterification, appear more resistant to hydrolysis. As a consequence, degradation residues obtained at the later stages of degradation are mainly composed of long glycolyl and caproyl sequences linked by -CGC- and -CGGGC- ones. The degradation rate of the copolymers depends also on the degree of crystallinity of each component which is related to the block length. The caproyl component can be preferentially degraded if it is in the amorphous state and the glycolyl component is semicrystalline. Introduction Aliphatic polyesters such as polylactide (PLA), poly(caprolactone) (PCL), and polyglycolide (PGA) have been extensively investigated for temporary therapeutic applications because of their outstanding degradability and biocompatibility.1-3 PLA is of great interest since its properties can be adjusted by varying the ratio of L-LA/D-LA enantiomers. PCL appears most attractive due to 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. On the other hand, PGA is a fast degrading polymer which is mainly used as suture material, owing to its high crystallinity and absence of practical solvents. A number of products derived from PLA, PGA, PCL, and various copolymers have reached the stage of clinical uses in the form of surgical sutures, bone fracture internal fixation devices, and drug delivery systems as well as tissue engineering scaffolds. PLA, PCL, and PGA polymers are synthesized by ring opening polymerization of corresponding cyclic lactones, i.e., lactide, -caprolactone, or glycolide, in the presence of an initiator such as stannous octoate, zinc metal, zinc lactate, * To whom correspondence should be addressed. (S.L.) Tel: +33 467 418266. E-mail:
[email protected]. (P.D.) Tel: +48 32 2716077. E-mail:
[email protected]. † Centre de Recherche sur les Biopolymeres Artificiels. ‡ Polish Academy of Sciences.
zirconium acetylacetonate, etc.4-9 The in vivo and in vitro degradation of aliphatic polyesters has been extensively investigated during the past two decades. It was established that degradation of large size devices is faster inside than at the surface because of the internal autocatalysis of carboxyl endgroups formed by chain cleavage.2,3,10-14 In the case of semicrystalline polymers, amorphous regions are preferentially degraded since water cannot penetrate crystalline zones.12,13 Degradation-induced compositional and morphological changes were also observed.12-14 In the case of PCL, the hydrolytic degradation is very slow due to its hydrophobicity and crystallinity.15,16 In the first part of this work, we reported the synthesis and characterization of copolymers obtained by ring-opening polymerization of glycolide and -caprolactone, using stannous (II) octoate and zirconium (IV) acetylacetonate as initiator. The effects of polymerization parameters on the chain microstructures and physicochemical properties were investigated. In this paper, we report on the hydrolytic degradation behaviors of these copolymers. Experimental Section Materials. PGA/PCL copolymers with different compositions and chain microstructures were synthesized as reported in the first part of this work.17 Measurements. The copolymer compositions and chain microstructures were examined by proton nuclear magnetic resonance (1H NMR) spectroscopy as previously described.18
10.1021/bm049458+ CCC: $30.25 © 2005 American Chemical Society Published on Web 11/23/2004
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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. Electron spray injection mass spectrometry (ESI-MS) experiments were carried out on degraded copolymers using a Finnigan LCQ ion trap mass spectrometer (Finnigan, San Jose USA). Copolymer samples were dissolved in DMSO at a concentration of 0.5 mg/mL and inserted into the electrospray interface at a flow rate of 2 µL/min. The voltage between the needle and the electrospray chamber was set to 4.5 kV. The capillary temperature was optimized to a limit of 200 °C. Mass spectra were acquired over the range of m/z 50-2000 in negative-ion mode. Differential scanning calorimetry (DSC) was performed from -70 to +230 °C 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. Capillary zone electrophoresis (CZE) data were collected using a P/ACE 5000 Beckman instrument equipped with UV absorbance detection at 254 nm and a fused-silica capillary (i.d. 75 µm, length 57 cm) with reverse mode. 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. A total of 20 µL of 0.5% (w/v) solution was injected for each analysis. The columns were calibrated with polystyrene standards (Polysciences, USA). For the copolymers insoluble in common organic solvents, 1,1,1,3,3,3-hexafluoro 2-propanol (HFIP) was used to evaluate inherent viscosity ([η]) changes. Measurements were conducted at 25 °C with a Ubbelohde viscometer. The concentration of the solutions was 2 mg/mL. Degradation. Films of the various copolymers were prepared by compression molding with a hydraulic press at 120-220 °C. Square specimens with dimensions of 10 × 10 × 0.5 mm which weighed about 60 mg were then cut from the films. For degradation studies, each specimen was placed in a vial filled with 5 mL of 0.13 M phosphate buffer (pH 7.4) containing 1.0 mg of sodium azide to prevent bacterial growth. The vials were placed in an oven thermostated at 37 °C. At each degradation time, three replicate specimens were withdrawn from the degradation medium and washed with distilled water. After wiping, the specimens were weighed and vacuum-dried at room temperature for one week, weighed again, and subjected to analysis. Water uptake and weight loss values are obtained according to the following equations: water uptake (%) ) [(Wwet - Wdry )/Wdry] × 100
(1)
weight loss (%) ) [(W0 - Wdry )/W0] × 100
(2)
Figure 1. Water uptake profiles of the PGA/PCL copolymers during degradation.
where Wwet, Wdry, and W0 represent, respectively, the wet weight (after degradation and wiping), dry weight (after vacuum-drying), and initial weight of the samples. The degradation of Cop6 which was in a waxy state was performed under similar conditions. Only the changes of composition and microstructure were examined. Results and Discussion Water Uptake and Weight Loss. The various copolymers behaved differently in the degradation medium taken as a model of body fluids. During degradation, Cop1 with high glycolyl content became more and more fragile. Cop 2 and Cop3 with intermediate compositions became deformable, sticky, and softened. Similar changes were observed for Cop5. Cop4 remained initially rigid but became fragile after 10 weeks. In contrast, Cop7, Cop8, and Cop9 with high caproyl contents remained rather rigid during degradation. Water uptake is the first phenomenon that occurs when a polymeric material is placed in an aqueous medium and reflects its bulk hydrophilicity. Figure 1 shows the water uptake profiles of the copolymers during degradation. Cop1, Cop2, and Cop3 showed initially a rapid increase of water uptake which reached 93% after 4 weeks for Cop2, 123% after 7 weeks for Cop3, and 104% after 15 weeks for Cop1. Cop5 absorbed 33% after 7 weeks. Beyond, it became impossible to make water uptake measurements since the samples became too fragile or sticky. Cop4 exhibited a slow but steady increase of water uptake which reached 30% after 26 weeks. In the case of Cop7, Cop8, and Cop9 with high caproyl contents, they exhibited a higher hydrophobicity with 7%, 13%, and 14% of water uptake after 26 weeks, respectively. Weight loss reflects the release of soluble oligomers formed during degradation as shown in Figure 2. Cop1 showed the fastest weight loss which attained 31% after 2 weeks and 56% after 26 weeks. Cop2 and Cop3 behaved similarly, weight loss increasing rapidly during the first 2 weeks, followed by a slower increase which reached 50% after 26 weeks. The other copolymers exhibited slower weight loss profiles. Weight loss of Cop4 was slightly faster than that of Cop5, 22% and 20% of initial material being lost after 26 weeks. In the case of Cop7, Cop8, and Cop9 with high caproyl contents, degradation appeared very slow
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Figure 2. Weight loss profiles of the PGA/PCL copolymers during degradation.
Figure 4. DSC thermograms of PGA/PCL copolymers: Cop2 (A) and Cop5 (B) after 0, 2, and 26 weeks’ degradation (a, first heating; b, second heating).
Figure 3. X-ray diffraction spectra of PGA/PCL copolymers: Cop2 (A) and Cop5 (B) after 0, 2, 15, and 26 weeks’ degradation.
with 6%, 8%, and 10% of weight loss after 26 weeks, respectively. X-ray Diffraction. The PGA/PCL copolymers are all semicrystalline materials. Their crystalline structure was examined by X-ray diffraction. Figure 3 presents the X-ray diffraction spectra of Cop2 and Cop5 which were synthesized under the same reaction conditions. Cop2 with a GG/C ratio of 48/52 initially exhibited two intense diffraction peaks at 11.0° and 14.4° characteristic of the PGA crystallites, and a small peak at 10.6° due to PCL crystallites. In fact, PCL homopolymer exhibits three diffraction peaks, an intense peak at 10.6° and two smaller peaks at 10.9° and 11.8°. The
two small peaks were not observed on the spectra of Cop2 because they were too weak to be detectable. In contrast, Cop5 with a GG/C ratio of 29/71 initially exhibited all the diffraction peaks characteristic of both the PGA and PCL crystallites, the peak at 10.9° of PCL overlapping the one at 11.0° of PGA. During degradation up to 26 weeks, changes were observed on the peak intensities as well as the areas of the amorphous background under the peaks. However, the crystalline structures remained unchanged. Similar findings were obtained in the case of the other copolymers. Thermal Properties. Thermal properties of the copolymers were investigated by DSC. Figure 4 shows the DSC curves of Cop2 and Cop5 after 0, 2, and 26 weeks’ degradation. Two runs were performed for each sample. Melting temperature (Tm) and melting enthalpy (∆Hm) were obtained from the first run, while glass transition (Tg) and crystallization temperature (Tc) were derived from the second run realized after quenching the molten sample. Cop2 exhibited initially a small melting peak at 50.0 °C with ∆Hm of 7.2 J/g and a large one at 216.0 °C with ∆Hm of 45.0 J/g which were assigned to the fusion of PCL and PGA crystallites, respectively. At the second heating, the PCL component presented a Tg at -43.6 °C, Tc at -21.6 °C, and Tm at 42.0 °C, while the PGA component presented 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
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the Tg and Tc of PGA. After 2 weeks’ degradation, Tm and ∆Hm of the PCL component remained nearly unchanged, whereas the PGA component presented a double melting peak at 191 and 200 °C with ∆Hm of 54.9 J/g. The increase in ∆Hm of PGA component is in agreement with the increase in GG/C ratio. At the second heating, Tg and Tc of both PCL and PGA components slightly increased with respect to initial data. Finally after 26 weeks, Tm and ∆Hm of the PGA component decreased to 198.3 °C and 36.5 J/g, in agreement with PGA degradation. Tm and ∆Hm of the PCL component increased to 60.3 °C and 22.8 J/g, which can be assigned to the fact that degradation of PGA resulted in a higher mobility of PCL blocks, thus allowing further crystallization. At the second heating, Tg and Tc of PCL decreased to -57.1 and -33.0 °C, whereas Tg and Tc of PGA increased to 26.0 and 71.0 °C. This is in agreement with the enhanced crystallizability of PCL and reduced crystallizability of PGA. In the case of Cop5, a large melting peak was detected at 43.7 °C with ∆Hm of 25.1 J/g and a small one at 192.7 °C with ∆Hm of 14.4 J/g. At the second heating, the PCL component presented a Tg at -55.1 °C, Tc at -24.3 °C, and a double melting peak at 18.0 and 27.0 °C. The PGA component presented a Tc at 50.7 °C and a Tm at 200.0 °C, with Tg being overlapped with the Tm of PCL in the 10 to 30 °C range. After 2 weeks’ degradation, Tm and ∆Hm of the PCL component remained nearly unchanged, whereas Tm of the PGA component decreased to 187.7 °C with ∆Hm of 15.9 J/g due to PGA degradation. At the second heating, Tg of PCL increased to -51.8 °C with Tc unchanged, whereas Tc of the PGA component increased to 64.7 °C. Finally after 26 weeks, Tm of the PGA component further decreased to 185.0 °C with ∆Hm of 19.8 J/g. Tm of the PCL component decreased to 39.0 °C with ∆Hm of 38.5 J/g. At the second heating, Tg and Tc of PCL increased to -48.1 and -16.0 °C, whereas Tc of PGA was not detected because the PGA component was so degraded that it cannot crystallize again after melting. Release of Soluble Oligomers. CZE was used to monitor water-soluble oligomers released into the degradation medium during degradation. Figure 5 shows the CZE traces of the degradation media with Cop2 or Cop5 after 2 and 26 weeks’ degradation. The monomer and oligomers were identified according to literature.19 After 2 weeks, an intense peak corresponding to glycolate monomer (G) was detected in the buffer solution. Other peaks with lower intensity were also observed, i.e., C, CG, CGG, CC, CCG, and CCC. It should be noted that the peaks of CGG could also result from GGC or GCG sequences, and that of CCG from GCC or CGC ones. Peaks A and B correspond to phosphate and cholate, respectively. Cholate was used as an internal reference. The intensity of peaks increased after 26 weeks’ degradation, except CGG which is easily degraded to yield CG and G. The small peak beside CG might be assigned to GC which is supposed to exhibit a slightly different mobility as compared to CG. Similar patterns were found for Cop5, although the intensity of the peaks is lower due to slower degradation. 1 H NMR Spectroscopy, ESI-MS Spectrometry and Inherent Viscosity Measurements. 1H NMR was used to
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Figure 5. CZE traces of the degradation media containing PGA/ PCL copolymers (Cop2 or Cop5) after 2 and 26 weeks’ degradation: A, phosphate; B, cholate.
monitor changes of copolymer composition and chain microstructure during degradation, whereas ESI-MS was employed to examine the structure of oligomers which were formed during degradation and were not dissolved in the degradation medium. On the other hand, inherent viscosity measurements were performed to follow the molar mass decrease of the copolymers (Figure 6). Table 1 shows the NMR and viscometric results obtained during degradation of Cop1. Two degradation phases can be distinguished. At the first phase (0-2 weeks), a rapid decrease of [η] and GG/C ratio was detected. In contrast, at the second phase, [η] decreased slowly and GG/C ratio increased. During the first 2 weeks (phase 1), the content of long glycolyl segments (mainly -GGGGGG- and -CGGGG-) decreased with GG/C ratio decrease. In the NMR spectrum, signal 3 increased as a consequence of slower degradation of -CGGGC- sequences. In the meantime, the content of long caproyl sequences -CC- increased. In this degradation phase, fast weight loss and water uptake as well as [η] decrease were observed. At the second degradation phase, both GG/C ratio and LG increased (Table 1), whereas weight loss and water uptake slowed (Figures 1 and 2). The increase of GG/C ratio could appear surprising because PGA homopolymer degrades much faster than PCL. The faster degradation of caproyl-rich sequences in the copolymer can be assigned to morphological differences between both components. In fact, both X-ray
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Table 1. Changes of Composition and Chain Microstructure with Degradation of Cop1 Containing 70% of Glycolyl and 30% of Caproyl Unitsa entry
time (weeks)
GG/C molar ratio
LG
LC
R
S (%)
M (%)
L (%)
[η] (dL/g)
[η]t/[η]0
1 2 3 4 5 6 7
0 2 4 7 10 15 26
70/30 57/43 59/41 72/28 82/18 87/13 89/11
5.8 4.0 4.2 7.6 12.6 21.4 ∼16.2
1.2 1.5 1.5 1.6 1.4 1.6 ∼1.0
1.00 0.93 0.93 0.75 0.79 0.69 1.00
8.2 7.1 6.0 3.4 2.5 2.8 2.8
20.5 21.4 24.1 6.7 8.5 16.7 17.9
53.3 44.7 44.6 73.9 78.9 73.5 73.3
0.46 0.28 0.25 0.22 0.18 0.13 0.05
1 0.60 0.55 0.47 0.39 0.28 0.11
a GG/C, molar ratio determined by 1H NMR; L , average length of glycolyl sequences; L , average length of caproyl sequences; R, degree of randomness; G C S, content of CGC sequence (signal 7 on the 1H NMR spectra); M, content of CGGGC (signal 3). GGGGC (signal 4), CGGGG + CGGGC (signal 5), and CGGC (signal 6) sequences; L, content of GGGGGG (signal 1) and CGGGG+GGGGC (signal 2) sequences; [η], inherent viscosity; [η]t/[η]0, relative inherent viscosity ([η]0, inherent viscosity before degradation).
Figure 6. Variations of relative inherent viscosity ([η]t/[η]0) with degradation.
diffraction and DSC data showed that the crystalline structure of the copolymer is of the PGA-type. In other words, the caproyl component is in the amorphous state due to its short block length (Table 1). ESI-MS analysis of the copolymer after 7 weeks’ degradation (maximum molecular weight, ca. 2 kDa) confirmed the presence of CnGm-type oligomers, where the values of n and m ranged from 2 to 10. No homooligomers Gn or Cn were detected at this stage. After 10 weeks, a large amount of CnGm oligomers were also detected. On the other hand, Gn homooligomers with n ranging from 7 to 16 were observed, whereas Cn oligomers were not present (Figure 7). These findings confirmed the conclusion obtained from the NMR analysis. Generally, sequences containing both glycolyl and caproyl units degrade faster than homosequences. Table 2 and Figures 8 present the degradation behaviors of the copolymers containing c.a. 50% of glycolidyl units with different chain microstructures (Cop2 and Cop3). The degradation of Cop2 with a more blocky structure (R ) 0.4) proceeded in three phases. At the first phase of degradation up to 4 weeks, GG/C ratio and LG increased (Table 2, entry 1-3), whereas sample weight and [η] strongly decreased (Figures 2 and 6). On the other hand, the content of long glycolyl sequences (L%) increased and that of short glycolyl ones (S%) decreased. The NMR analysis showed that at this phase, the relative intensity of -CGGC- (Figure 8A, signal 6) decreased, and that of CGGGC increased. Moreover, -CC- sequences exhibited a strong decrease, which is in
agreement with their nearly amorphous state as shown by DSC and X-ray diffraction. In the second phase up to 10 weeks (Table 2, entry 3-5), GG/C ratio and LG decreased. NMR spectra showed that -GGGGC- and -CGGC- sequences (signals 4 and 6) decreased. In the third phase up to 26 weeks (Table 2, entry 5-7), GG/C ratio increased again. Interestingly, both LG and LC increased, in agreement with the decrease of the degree of randomness. Signals 4 and 6 almost disappeared. Only signals of slowly degrading groups such as -CGC- (signal 7) or -CGGGC- (signals 3 and 5), longer Gn (signals 1 and 2) and Cn sequences (signal 9) remained. Additional signals were also detected at 4.78, 4.40, and 4.12 ppm which could be assigned to end units of oligomers. ESI-MS investigation of the copolymer Cop2 after 7 weeks’ degradation revealed the presence of CnGm oligomers (n ) 3-13 and m ) 1-7). The main fraction consisted of C7G4, C8G3, and C8G4 sequences. Homooligomers were not present. Beyond 10 weeks, the obtained spectra were characterized by the presence of lines of CnG and CnG2 sequences with n ) 1-16 and a small amount of Cn oligomers. These findings confirmed the faster degradation of sequences consisting of both glycolyl and caproyl units, in agreement with CZE data showing the presence of G, C, CG, CGG, CC, CCG, and CCC species (Figure 5). Gn homooligomers were not detected. The degradation process of Cop3 with a more randomized microstructure proceeded differently (Table 2, entries 1A7A, Figure 8B). During the first 10 weeks, GG/C ratio, LG, and long glycolyl sequences (L%) decreased. This finding can be related to the fact that the glycolyl component was only slightly crystalline, in contrast to Cop2. The inherent viscosity decreased rapidly as in the case of Cop2. In fact, Cop2 and Cop3 degraded faster than the other copolymers (Figure 6). Between 10 and 26 weeks, GG/C ratio, LG, and long glycolyl sequences (L%) increased. On the NMR spectra, the relative intensity of signal 7 (CGC) remained almost unchanged, and that of signals 1 and 2 (GGGGGG and CGGGG + GGGGC) decreased first and then increased. Signal 3 (CGGGC) initially undetected appeared after degradation, whereas signals 4 (GGGGC), 5 (CGGGG + CGGGC), and 6 (CGGC) decreased almost continuously. On the other hand, the GC signal was initially higher than the CC one due to the highly randomized structure. During degradation, the relative intensity of the GC signal decreased as compared to that of CC. This finding indicates that G-C
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Figure 7. ESI-MS spectrum of Cop1 after 10 weeks’ degradation. Table 2. Changes of Composition and Chain Microstructure with Degradation of PGA/PCL Copolymers Containing ca. 50% of Glycolyl and 50% of Caproyl Units (Entries 1-7 for Cop2; Entries 1A-7A for Cop3)a entry
time (weeks)
GG/C molar ratio
LG
LC
R
S (%)
M (%)
L(%)
[η] (dL/g)
[η]t/[η]0
1 2 3 4 5 6 7 1A 2A 3A 4A 5A 6A 7A
0 2 4 7 10 15 26 0 2 4 7 10 15 26
48/52 64/36 68/32 60/40 57/43 60/40 66/34 47/53 32/68 33/67 31/69 32/68 36/64 41/59
7.0 7.8 9.4 6.6 7.8 10.2 22.4 2.6 1.4 1.4 1.4 1.2 1.8 2.8
3,7 2.2 2.2 2.2 3.0 3.3 5.8 1.4 1.4 1.4 1.4 1.3 1.6 2.0
0,40 0.59 0.55 0.59 0.47 0.39 0.22 1.14 1.50 1.43 1.50 1.62 1.19 0.85
5,2 4.7 1.6 3.8 2.9 4.5 3.2 15.4 14.4 16.0 17.9 18.7 15.9 15.1
14,3 14.0 14.6 15.0 14.6 15.0 14.4 23.0 21.6 21.0 16.9 17.3 13.3 11.6
45,5 59.3 64.8 56.3 55.5 55.5 62.4 25.6 12.0 8.0 7.5 7.2 23.9 31.3
0,44 0.21 0.11 0.07 0.04 0.02
1 0.47 0.24 0.16 0.08 0.05
0.53 0.32 0.17 0.07 0.03 0.02
1 0.60 0.32 0.13 0.05 0.04
a
See Table 1 for abbreviations.
bonds are preferentially cleaved with respect to C-C bonds, with caproyl component being in the amorphous state. ESI-MS analysis shows the presence of widely distributed CnGm oligomers (n ) 1-12 and m ) 2-10) with a maximum for C7G6 and C7G7 oligomers after 7 weeks’ degradation. Beyond this time, the spectra remained almost unchanged, with C8G7 and C8G8 oligomers constituting the most abundant fraction. Nevertheless, the fraction of lower molar mass oligomers decreased. No Cn or Gm homooligomers were detected. These data indicate that degradation of Cop3 proceeded more homogeneously than that of Cop2 due to its more randomized chain microstructure. The degradation of copolymers containing ca. 30% of glycolidyl units (Cop4, 5, and 6) is presented in Table 3 and Figure 9. The three copolymers with various microstructures were examined: partly blocky Cop4 with longer glycolidyl microblocks, segmental Cop5 consisting mainly of longer GGGGGG-type sequences as well as shorter CGC ones, and nearly random Cop6. The decrease of the GG/C ratio was much faster for Cop4 than for Cop5 and Cop6 during the
first two weeks (Table 3, entry 1-2). Degradation at this stage proceeded with the decrease of content of longer -GGGGGG- glycolyl sequences (signal 1). The initial average lengths of glycolyl sequences (LG) of Cop4, Cop5, and Cop6 were much shorter than those of Cop1 and Cop2. X-ray diffraction and DSC analyses (Figures 3 and 4) showed that both glycolyl and caproyl components of Cop4 and Cop5 are partly crystalline, whereas Cop6 is totally amorphous. In these cases, the glycolyl component degraded faster than the caproyl one. The GG/C ratio decreased almost continuously for Cop4 and Cop6, whereas it decreased during the first 2 weeks and then remained almost unchanged for Cop5. Figure 9A shows that all glycolyl signals decreased with degradation except signals 3 and 7. The relative intensity of GC also decreased as compared to that of the CC one, in agreement with the increase of LC value and the preferential cleavage of G-C bonds. In the case of Cop5, the spectra showed little changes during degradation. This finding could be assigned to the
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Polymerization of PGA and PCL. Part 2
Figure 8.
1H
NMR spectra of PGA/PCL copolymers: Cop2 (A) and Cop3 (B) after 0, 2, 10, and 26 weeks’ degradation.
Table 3. Changes of Composition and Chain Microstructure with Degradation of PGA/PCL Copolymers Containing ca. 30% of Glycolyl and 70% of Caproyl Units (Entries 1-7 for Cop4, Entries 1A-7A for Cop5, and Entries 1B-5B for Cop6)a entry
time (weeks)
GG/C molar ratio
LG
LC
R
S (%)
M (%)
L (%)
[η] (dL/g)
[η]t/[η]0
1 2 3 4 5 6 7 1A 2A 3A 4A 5A 6A 7A 1B 2B 3B 4B 5B
0 2 4 7 10 15 26 0 2 4 7 10 15 26 0 2 7 9 17
27/73 17/83
3.2 2.0
4.2 4.7
0.54 0.72
6.0 4.4
9.9 9.3
27.1 15.4
19/81 17/83 16/84 11/89 29/71 24/74
2.0 2.0 2.0 1.4 2.0 1.8
4.6 5.0 5.0 5.8 2.5 2.8
0.67 0.68 0.72 0.86 0.88 0.93
4.5 4.4 3.9 3.4 16.2 15.6
9.9 8.7 6.4 3.8 7.7 7.8
17.6 16.0 17.6 12.8 21.2 15.6
25/75 22/78 24/76 23/77 29/71 25/75 23/77 21/79 17/83
1.8 1.6 1.8 1.8 1.6 1.3 1.1 1.1 ∼1
2.7 2.9 2.8 3.1 2.1 1.9 1.8 2.2 2.3
0.93 0.97 0.93 0.87 1.05 1.32 1.50 1.32 1.49
14.8 14.4 15.2 15.2 20.3 19.6 17.8 19.6 19.4
7.6 5.8 6.6 5.9 21.2 18.0 17.4 14.7 9.6
17.6 15.8 17.2 15.9 3.6 2.4 1.9 0.7 0
0.78 0.57 0.53 0.43 0.39 0.29 0.17 0.83 0.67 0.56 0.46 0.32 0.25 0.17 0.91 0.68 0.39
1 0.73 0.68 0.55 0.50 0.37 0.22 1 0.80 0.67 0.55 0.38 0.30 0.20 1 0.74 0.43
0.19
0.21
a
See Table 1 for abbreviations.
high content of CGC sequences (signal 7) which degrade more slowly than other glycoyl sequences. The degradation of copolymers with ca. 10% of glicolidyl units (Cop7, Cop8, and Cop9) proceeded very similarly. Degradation was slower than the other copolymers with lower caproyl contents (Figure 6). NMR spectra showed little changes of chain microstructures during degradation. Cop7
contained a small percentage of long glycoyl sequences (1.9%) which were preferentially degraded as compared to CGC ones. During the whole degradation period, the glycolyl component only slightly decreased. On the other hand, SEC data showed that the molar mass distribution remained almost unchanged, indicating that degradation proceeded homogeneously.
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Figure 9.
1H
Li et al.
NMR spectra of PGA/PCL copolymers: Cop4 (A) and Cop5 (B) after 0, 2, 10, and 26 weeks’ degradation.
Figure 10. Dependence of the 1/2 inherent viscosity decrease time on glycolidyl units content.
Conclusion The results presented above show that the degradation rate of glycolide/-caprolactone copolymers depends not only on the copolymer composition but also on the chain microstructure. This conclusion is illustrated in Figure 10 showing the dependence of 1/2 inherent viscosity decrease time on the glycolidyl content. Cop2 and Cop3 containing ca. 50% glycolidyl units degraded the most rapidly. The degradation rate of Cop1 (about 70% of glycolidyl units) and completely randomized Cop6 (30% of glycolidyl units) was slower than that of Cop2 and Cop3. The copolymers with the same gross composition as Cop6 but with a more blocky chain micro-
structure, Cop4 and Cop5, degraded less rapidly than Cop6. Generally, copolymers with higher C-G bonds content or higher degree of randomness exhibited higher degradation rate. Unexpectedly, sequences with odd numbers of glycolyl units such as -CGC- and -CGGGC- which resulted from second mode transesterification, appeared more resistant to hydrolysis. As a consequence, degradation residues obtained at the later stages of degradation were mainly composed of long glycolyl and caproyl sequences linked by -CGC- and -CGGGC- ones. The degradation rate of the copolymers depends also on the degree of crystallinity of each component which is related to the block lengths. The caproyl component in the amorphous state can be preferentially degraded in comparison with semicrystalline glycolyl component. Therefore, the degradation rate of PGA/PCL copolymers can be varied by using different synthesis conditions which lead to various chain microstructures. This is of major importance for applications in the domains of surgery, pharmacology as well as tissue engineering. 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.
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