Synthesis and Characterization of a Novel Functional Biodegradable Copolymer-Poly(lactic acid-4-hydr

Chinese Chemical Letters Vol. 17, No.8, pp 1125-1128, 20061125http://www.imm.ac.cn/journal/ccl.htmlSynthesis and Characterization of a Novel Functional BiodegradableCopolymer - Poly(lactic acid-4-hydroxyproline-polyethylene glycol)Jiu Fang DUAN, Yu Bin ZHENG*Department of Polymer Science, Dalian University of Technology, Dalian 116012Abstract: A series of poly(lactic acid-4-hydroxyproline-polyethylene glycol) (PLA-Hpr-PEG)copolymers were synthesized by direct melt copolymerization of D,L-lactic acid and 4-hydroxy-proline with different feed amount of polyethylene glycol (PEG) 0.1%， 0.5%， 1% and 5%,respectively. The properties of these copolymers were characterized by using IR spectroscopy,proton nuclear magnetic resonance (H-NMR) spectroscopy, gel permeation chromatography(GPC)，X-ray diffaction and differential scaning calorimetry (DSC). PLA-Hpr-PEG areamorphous copolymers. Copolymers showed increasing water uptake capacity with increasingPEG percentage in the feed, which result in an increasing degradable rate in phosphate buffersolution (pH 7.4) at 37°C.Keywords: Lactic acid, 4-hydroxyproline, polyethylene glycol.Polylactid (PLA) and its copolymers with glycolid caprolactone have been extensivelyused as biodegradable carriers for drug delivery' .2 . These biodegradable aliphaticpolyesters, with proven biocompatibility， have versatile biodegradation propertiesdepending on their molecular weight and chemical compositions'. Nevertheless, therehave been many attempts to improve the properties of the polymer to make them suitablefor a specific application. We synthesized amphipathic PLA-Hpr-PEG copolymerswhich bearing pendant functional groups that available for attachment of bioactivepeptides or other further chemistry by the copolymerization of functional monomers.Scheme 1 Structure of PLA-Hpr-PEGdCH一 CH2gCH2 CH2 CO一-CH-C-O- +(CH2CH2)+ OHaCH3H中国煤化工YHCNMH G*E-mail: zybwl@ 163.com1126Jiu Fang DUAN et al.ExperimentalLactic acid was purchased as 90% aqueous solution from Shanghai Chemical Industries.Glycolic acid and 4-hydroxyproline were purchased from Tianjing Chemical Industries.Polyethylene glycol was purchased from Guangzhou Chemical Industries.Tin(I)chloride dihydrate and p-tolulenesulfonic acid monohydrate (TSA) were purchased fromGuangzhou Chemical Industries, and all these materials were used without purification.All other chemicals were purchased in analytical grade made in China.IR spectra were measured on a NICOLET-20DXB IR spectrophotometer. Sampleswere pressed into KBr pellets. 'H NMR spectra were measured on a Varian INOVA400MHz spectrometer in DMSO, containing 1 vol. % of tetramethylsilane (TMS) as theinternal reference. The crystallinity of the polymer was carried out on a XD3-AWide-angle X-ray diffraction (WAXD) apparatus.Gel permeation chromatographic(GPC) analysis was performed at 40°C on Waters apparatus equipped with ShodexKF-800 columns at a rate of 1mL/min.THF was served as solvent and a differentialrefractometer as detector. Polystyrene-standards were used for calibration. Differentialscanning calorimetry (DSC) measurements were carried out at a heating rate of 10°C /min on a 910S thermal analyzer with N2 gas protection. Contact angle of polymer filmswere measured statically on a JY-82 contact angle meter (Made in China). And watersorption was evaluated by immersing polymer films in distilled water for 72 h at roomtemperature and calculated as follows:Water sorption (%)={[W wer- _W dry]/ W dry} x 100%Where Wwet was the weight of the polymer film just being taken out of the water afterremoving the surface water by filter paper, and W dry was the weight of the wet film afterrigorously drying in vacuum at room temperature.Lactic acid (8.0 mmol) was dehydrated at 150°C, at a pressure of 5 mmHg for 6 h.Then，the oligomer was crash into power and put it into a 250 mL flask, and4-hydroxy-1-oxoethyl-L-prolinet (4 wt%), PEG (0.1-5%) were mixed with 2.5 wt% tin(I)chloride dihydrate and TSA. The mixture was heated at 180°C under mechanicalstirring at 5 mmHg for a predetermined time. At the end of the reaction, the flask wascooled down, the product was dissolved in acetone and subsequently precipitated indistilled water.The resulting solids were filtered and dried in vacuum. At last, theprotected amino group was reduced by 5 wt% palladium-on-charcoal catalyst. Thecompositions in the copolymers were analyzed by IR spectroscopy (Figure 1) and 'H-NMR spectroscopy (Figure 2). In the region of protons, well resolved signals areobserved: The absorption peaks (δ 5.25 ppm) is the methane (C4-H) of the proline. Themethine proton of the PEG is shown at δ 3.66 ppm, the absorption peaks(δ 1 .49 ppm) isthe methyl (C2-CH3) of the lactic acid in PLA- N-Ace-Hpr.中国煤化工Results and DiscussionMYHCNMH GPEG content increased, due to too active end groups lead to chain transfer, the growingSynthesis and Characterization of Poly(lactic acid-4-hydroxyproline- 1127polyethylene glycol)Figure 1 IR spectra of Hpr (a); N-ace -Hpr(b); PLA-N-Ace-Hpr (c); PLA-Hpr- PEG (d)a(T%rd300020001000Waveumbers (cm-1)Figure 2 H-NMR spectra of PLA-Hpr-PEGbcgdppm7642active end group was cut out in chain transfer to make the molecular weight to decrease. .We synthesized the PLA-Hpr PEG polymers by the melt polymerization method. Underthe same reaction temperature, the polymer with high molecular weight tended to givehigher viscosity, resulting in lower homogeneity and caused high scattered distribution ofmolecular weight. The molar ratio of the monomers in the molcular chain was closedto what designed, as shown in Table 1. There was lttle effect on the Tg and contactangle of the copolymer when the content of PEG changed from 0. 1% to 5%.The crystalline behavior of PLA-Hpr-PEG copolymers was tested by X-raydiffraction measurements. There are two continuous intensity distribution “obtusepeaks", this is typical diffraction curve of amor中国煤化Iallinity ofcopolymers is dependent on the type and the mYHCNMH G monomercomponents in the copolymer chain. The crystaunt vtudV 1UIUl uic upolymers isdifferent from that of the traditional poly(lactic acid-polyethylene glycol) (PLA-PEG)1128Jiu Fang DUAN et al.copolymers. This is may be for two reasons: one is the molecular weight of thecopolymer is low, and the other is the regularity of the molecular chain was destroyed by4-hydroxyproline.In vitro the release behavior of PLA-Hpr-PEG copolymers is diffrent fromtraditional PLA-PEG copolymers. The low molecular weight and the amorphousproperties of PLA-Hpr-PEG (copolymers 1, 2, 3 and 4) might promote the degradationspeed of the copolymers.Table 1 Copolymerization results of lactic acid and 4-hydroxyproline with PEGSample_ Lactic acid/4-hydroxy proline/PEG (wt%) MwMw/ Contact TgYieldFeeding doseProductMn angle(C) (C) (%)96/4/0.193.56/ 4.13/ 0.0713610 1.70 36.3532.57396/ 4/ 0.593.84/ 4.32/ 0.4513446 1.63 34.0530.396/4/ 1.094.62/ 4.27/ 0.8612932 1.53 33.8029.0 6896/ 4/ 5.094.44/ 4.35/ 4.7797051.32 33.6427.0a. Determined by 'H-NMR.ConclusionNew amphipathic copolymers from lactic acid, 4-hydroxyproline and polyethyleneglycol were synthesized via direct melt copolymerization.The pendant functionalgroups make the copolymers to be able to attach to either drugs or biologically activeagents. The yield of the new polymer produced was more than 67%. The copolymerssynthesized exhibited moderate molecular weights (Mn = 9705-13610 g'mol-) withreasonable molecular weight distributions (Mw/Mn= 1.32- 1.70).n summery， the functional novel amphipathic polymer prepared by meltpolycondensation is expected to be used in drug control and delivery system. Furtherinvestigations are under way to examin the proteins or peptide drug release behaviorfrom these block copolymers.References1. H. Yoshizawa, S. Nishino, K. Shiomori, et al, International Journal of Pharmaceutics, 2005,296(1-2), 112.Y. Hong, C. Gao, Y. Xie, et al, Biomaterials, 2005, 32(26), 6305.A. A. Ignatius, L. E. Claes, Biomaterials, 1996, 17, 83.4. Y. K. Heewon, L. Robert, Macromolecules, 1989, 22, 3250.Received 24 February, 2006中国煤化工MYHCNMH G