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Synthesis of novel poly(ethylene glycol) based amphiphilic polymers
European Polymer Journal 39 (2003) 1983–1990 www.elsevier.com/locate/europolj
Synthesis of novel poly(ethylene glycol) based amphiphilic polymers Kunya Danprasert a, Rajesh Kumar a,b, Ming H-Cheng a, Pankaj Gupta c, Najam A. Shakil a,c, Ashok K. Prasad c, Virinder S. Parmar a,c, Jayant Kumar b, Lynne A. Samuelson d, Arthur C. Watterson a,* a
d
Department of Chemistry, Institute for Nano Science and Engineering Technology, University of Massachusetts, Lowell, MA 01854, USA b Center for Advanced Materials, Department of Chemistry, University of Massachusetts, Lowell, MA 01854, USA c Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India Natick Soldier Center, US Army Soldier and Biological Chemical Command, Kansas Street, Natick, MA 01760, USA Received 6 March 2003; received in revised form 16 May 2003; accepted 16 May 2003
Abstract The synthesis of new amphiphilic polyesters based on poly(ethylene glycol) (PEGs) and studies on their solution properties are reported. Two novel monomers, dimethyl 5-n-butoxy isophthalate (2) and dimethyl 5-n-octoxy isophthalate (3) were synthesized. Three series of novel amphiphilic polyesters, i.e. poly(ethyleneoxy isophthalate)s (10–15), poly(ethyleneoxy n-butoxy isophthalate)s (16–21) and poly(ethyleneoxy n-octoxy isophthalate)s (22–27) have been synthesized from PEGs of different sizes and dimethyl isophthalates 1–3 via the transesterification–polycondensation using dibutyltin diacetate as a catalyst. The structures of the polyesters were established from a detailed analysis of their spectra, i.e. FTIR, 1 H-NMR (one- and two-dimensional) and 13 C-NMR. By adjusting the ratio of hydrophobic (diesters) and hydrophilic (PEGs) segments in polymers, their main chain structures and solution properties could be changed. The viscosity molecular weights (Mv ) of polymers, obtained from Mark–Houwink–Sakurada relationship having poly(ethylene terephthalate) as a model, were in the range of 4500–32,000 g/mol. Intrinsic viscosities were studied based on polymer backbone length (PEGs effect) and pendant group (diesters effect) and these were found to be dependent on molecular weights of the PEGs used. Ó 2003 Elsevier Ltd. All rights reserved.
1. Introduction The unique properties of poly(ethylene glycol) (PEG), including a wide range of solubility, lack of toxicity, absence of antigenicity and immunogenicity, non-interference with enzymatic activities and conformations of polypeptides, and ease of excretion from living organisms, make them ideal drug carriers [1,2]. The
* Corresponding author. Tel.: +1-978-934-3691; fax: +1-978458-9571. E-mail address: [email protected] (A.C. Watterson).
two-hydroxyl end groups of PEG have been suitably functionalized prior to coupling [3] with ligands of biological relevance, although the hydroxyl groups themselves have been used as well [4–7]. Because the number of terminal groups of PEGs (only two) to attach with drugs limits their drug loading capacity, extensive work has been done to functionalize them by copolymerizing PEGs with various functional monomers. Amphiphilic block copolymers with hydrophilic and hydrophobic segments have been investigated extensively not only because of their unique self-organization characteristics but also for their wide range of potential applications, such as in drug delivery and separation technology systems [8]. The micellar characteristics of
0014-3057/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0014-3057(03)00111-3
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K. Danprasert et al. / European Polymer Journal 39 (2003) 1983–1990
amphiphilic diblock copolymers depend on the nature of each block and the surface properties of self-organized micelles are highly dependent on the structures of the hydrophilic blocks [9–11]. Kwon et al. [12,13] synthesized AB block copolymers of poly(ethylene oxide) (PEO) and poly(b-benzyl-L aspartate) (PBLA). The distribution of hydrophobic moieties into the PEO–PBLA micelles was investigated by UV spectroscopy using pyrene as a model. Recent efforts in the design of drug delivery systems have led to the development of vehicles that circulate for prolonged periods in the vascular system. A common feature of the new drug vehicles is PEO at their surfaces. PEO is a nontoxic, highly hydrating polymer (through hydrogen bonding) that sterically stabilizes surfaces in aqueous systems, and this is effective for preventing the adsorption of proteins and adhesion of cells [14]. In this work, we report the synthesis of new class of amphiphilic copolymers by transesterification–polycondensation of hydrophilic PEGs and hydrophobic functionalized dimethyl 5-hydroxy isophthalate monomers and their solution properties. The polymeric system and design described in this paper are very unique and highly flexible as compared to already reported PEG based systems. Most of the PEG modified systems are diblock polymeric systems. The flexibility in adjusting the ratio of hydrophilic segments (PEGs) and hydrophobic segments (modified diester compounds) provides easy access to tailor the polymer solution properties. PEGs of different sizes were used for the polymerization as well as three different sets of hydrophobic monomers were used. The critical micelle concentration (CMCs) values of polymers have been investigated and determined by surface tension measurements. Intrinsic viscosities were studied based on polymer backbone length (PEGs effect) and nature of the pendant group (diesters effect) and these were found to be dependent on molecular weights of the PEGs.
2. Experimental
concentration used was 4% w/v in chloroform-d. Carbon-13 (13 C)-NMR spectra were recorded at 62.5 MHz on a Bruker spectrometer in 20% w/v chloroform-d solutions. The chemical shifts in ppm are referenced relative to the internal standard chloroform-d at 77.00 ppm. 2.3. Infrared spectroscopy A Perkin-Elmer 1760 FTIR spectrometer was used to obtain the spectra after 32 scans (8 cm1 resolution) over the range 4000–400 cm1 . Liquid films on a NaCl pellet and potassium bromide pellets were used for sample preparation. 2.4. UV–visible spectroscopy A UV–visible 916, GBC Scientific equipment, with double beams and direct ratio recording system was used to determine absorbance of samples. The spectrometer was equipped with 50 W tungsten–halogen and 30 W deuterium lamps and a silicone photodiode detector. 2.5. Solution properties Viscosities were investigated to study polymer solution properties. All polymer viscosities were determined under semi-concentration (5.0% w/v) and dilute concentration (0.1% w/v) using water as a media. The viscosity shear rate relationships of the polymers were measured by a Wells–Brookfield cone and plate model HATDCP digital viscometer having 0.8° cone and 0.5 ml sample size at 25 °C. Dilute solution viscosity (intrinsic viscosity) measurements were obtained by an Ubbelohde dilution viscometer maintained in a water bath at a constant temperature of 25.0 0.1 °C. 2.6. Surface tension measurements All polymer solutions were prepared in distilled water and the CMCs were determined using a Fisher Scientific Surface Tensiomat 21.
2.1. Materials All the chemicals and solvents were purchased from Aldrich Chemical Co. and used as received unless otherwise specified. PEGs and monomers were dried in a vacuum oven overnight before use. 2.2. Nuclear magnetic resonance spectroscopy (NMR) Proton (1 H)-NMR spectra were recorded on a Bruker spectrometer at 250 MHz. The chemical shifts in parts per million (ppm) are reported downfield from 0.00 ppm using tetramethylsilane as an internal reference. The
2.7. Synthesis of dimethyl 5-n-octoxy isophthalate (3) To a solution of dimethyl 5-hydroxy isophthalate (5.0 g, 23.8 mmol) in DMF (200 ml) was added fused potassium carbonate (6.5 g, 47.2 mmol) and the contents stirred for 1 h at 80 °C under nitrogen atmosphere. To this mixture, a solution of 1-bromooctane (4.6 g, 23.8 mmol) in DMF (50 ml) was added and the mixture was allowed to stir for 6 h and the progress of reaction was monitored by thin layer chromatography using a solvent system of ethyl acetate and hexane. After completion, the solvent was removed under reduced pressure on a
K. Danprasert et al. / European Polymer Journal 39 (2003) 1983–1990
1985
It was also synthesized as a white solid as described above. 1 H-NMR (CDCl3 ): d 0.95 (3H, C-10H), 1.55 (2H, C9H), 1.83 (2H, C-8H), 3.95 (6H, 2 OCH3 ), 4.08 (2H, C-7H), 7.70 (2H, C-2H and C-6H) and 8.25 (1H, C-4H). 13 C-NMR (CDCl3 ): d 14.07 (C-10), 19.52 (C-9), 31.51 (C-8), 52.63 (OCH3 ), 68.74 (C-7), 120.25 (C-2 and C-6), 123.13 (C-4), 132.14 (C-3 and C-5), 159.67 (C-1) and 166.55 (COO). FTIR (cm1 ): 2956, 2875, 1728 (COO), 1595, 1457, 1435, 1340, 1242, 1117, 1036 and 758.
butyltin diacetate (as catalyst, 5.0% w/w) was stirred at 120–130 °C for 2 h under nitrogen atmosphere. The mixture was then heated to 200 °C and allowed to react at this temperature for 30 min, the reaction was continued under reduced pressure (less than 1 mmHg) for an additional 2 h. The crude product was dissolved in tetrahydrofuran and precipitated with hexane, the precipitate so obtained was redissolved in water to remove any traces of unreacted isophthalates (as these are not water soluble) and then placed in a dialysis bag having a MWt cut off at 1000 Da. The final product [poly(tetraethyleneoxy isophthalate), 10] was obtained as a viscous oil. 1 H-NMR (CDCl3 ): d 3.60–3.70 (m, C-9H and C10H), 3.90 (t, 2H, C-8H), 4.50 (t, 2H, C-7H), 7.55 (t, 1H, C-1H), 8.25 (d, 2H, H-2 and H-6) and 8.70 (s, 1H, C4H). 13 C-NMR (CDCl3 ): d 62.38 (C-10), 62.44 (C-9), 64.41 (C-8), 71.40 (C-7), 130.0 (C-1, C-2 and C-6), 132.0 (C-3 and C-5), 136.0 (C-4) and 168.0 (COO). FTIR (cm1 ): 3495 (OH), 2872, 1724 (COO), 1609, 1455, 1355, 1304, 1235, 1127, 937, 868, 732 and 519. Other poly(ethyleneoxy isophthalate)s synthesized were poly(hexaethyleneoxy isophthalate) (11), poly(ethyleneoxy-400 isophthalate) (12), poly(ethyleneoxy-600 isophthalate) (13), poly(ethyleneoxy-900 isophthalate) (14) and poly(ethyleneoxy-1500 isophthalate) (15) by the polycondensation of dimethyl isophthalate and the corresponding PEGs of different molecular weights by the above mentioned procedure, the isolated yields in all these reactions were around 80% (Table 1).
2.9. Synthesis of poly(tetraethyleneoxy isophthalate) (10)
2.10. Synthesis of poly(ethyleneoxy n-alkoxy isophthalate)s (16–27)
A mixture of dimethyl isophthalate (1, 2.90 g, 0.015 mol), tetraethylene glycol (5.83 g, 0.03 mol) and di-
Synthesis of poly(tetraethyleneoxy n-octoxy isophthalate), 22: This was synthesized via transesterification
vacuum rotavapor, followed by the addition of water. The product was extracted with CH2 Cl2 . The organic layer was collected and dried over anhydrous magnesium sulfate. The solvent was then removed to give a white solid powder, which recrystallized from methanol to give a white crystalline solid. 1 H-NMR (CDCl3 ): d 0.89 (3H, C-14H), 1.20–1.35 (10H, C-9H to C-13H), 1.85 (2H, C-8H), 3.95 (6H, 2 OCH3 ), 4.13 (2H, C-7H), 7.76 (2H, C-2H and C-6H) and 8.20 (1H, C-4H). 13 C-NMR (CDCl3 ): d 14.35 (C-14), 22.96 (C-12 and C-13), 26.32 (C-10 and C-11), 29.46 (C-9), 32.13 (C-8), 52.62 (OCH3 ), 69.06 (C-7), 120.25 (C-2 and C-6), 123.13 (C-4), 132.15 (C-3 and C-5), 159.67 (C-1) and 166.54 (COO). FTIR (cm1 ): 2928, 2857, 1729 (COO), 1595, 1456, 1435, 1340, 1314, 1241, 1118, 1104, 1049, 1006 and 759. 2.8. Synthesis of dimethyl 5-n-butoxy isophthalate (2)
Table 1 Effect of PEG chain length on the Mv , CMC and DP of poly(ethyleneoxy isophthalate)s Monomer (diester)
Poly(ethylene glycol)
Polyester
Avg [g] (dl/g)
DP (avg)
CMC (mmol)
Dimethyl isophthalate (1)
Tetraethylene glycol (4)
Poly(tetraethyleneoxy isophthalate) (10) Poly(hexaethyleneoxy isophthalate) (11) Poly(ethyleneoxy-400 isophthalate) (12) Poly(ethyleneoxy-600 isophthalate) (13) Poly(ethyleneoxy-900 isophthalate) (14) Poly(ethyleneoxy-1500 isophthalate) (15)
0.1652
24
–
7800
0.1935
24
0.31
9700
0.2197
22
0.50
12,000
0.3259
27
0.31
19,900
0.3393
20
0.34
21,000
0.4604
20
0.25
32,000
Hexaethylene glycol (5) Poly(ethylene glycol)-400 (6) Poly(ethylene glycol)-600 (7) Poly(ethylene glycol)-900 (8) Poly(ethylene glycol)-1500 (9)
Mv (g/mol)
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K. Danprasert et al. / European Polymer Journal 39 (2003) 1983–1990
Table 2 Effect of PEG chain length on the Mv , CMC and DP of poly(ethyleneoxy alkoxy isophthalate)s Monomer (diester)
PEG
Polyester
Avg [g] (dl/g)
DP (avg)
CMC (mmol)
Dimethyl 5-n-butoxy isophthalate (2)
Tetraethylene glycol (4)
Poly(tetraethyleneoxy butoxy isophthalate) (16) Poly(hexaethyleneoxy butoxy isophthalate) (17) Poly(ethyleneoxy-400 butoxy isophthalate) (18) Poly(ethyleneoxy-600 butoxy isophthalate) (19) Poly(ethyleneoxy-900 butoxy isophthalate) (20) Poly(ethyleneoxy-1500 butoxy isophthalate) (21)
0.1096
11
–
4500
0.1178
10
2.53
4900
0.1672
13
0.81
8000
0.2130
14
0.68
11,000
0.2842
15
0.59
16,000
0.3610
14
0.31
24,000
Poly(tetraethyleneoxy octoxy isophthalate) (22) Poly(hexaethyleneoxy octoxy isophthalate) (23) Poly(ethyleneoxy-400 octoxy isophthalate) (24) Poly(ethyleneoxy-600 octoxy isophthalate) (25) Poly(ethyleneoxy-900 octoxy isophthalate) (26) Poly(ethyleneoxy-1500 octoxy isophthalate) (27)
0.1152
11
–
4800
0.1114
9
1.35
4600
0.1494
10
0.96
6800
0.1854
11
0.70
9100
0.1794
8
0.78
8800
0.2984
10
0.39
18,000
Hexaethylene glycol (5) Poly(ethylene (6) Poly(ethylene (7) Poly(ethylene (8) Poly(ethylene (9)
Dimethyl 5-n-octoxy isophthalate (3)
glycol)-400 glycol)-600 glycol)-900 glycol)-1500
Tetraethylene glycol(4) Hexaethylene glycol (5) Poly(ethylene (6) Poly(ethylene (7) Poly(ethylene (8) Poly(ethylene (9)
glycol)-400 glycol)-600 glycol)-900 glycol)-1500
between dimethyl 5-n-octoxy isophthalate (3, 4.83 g, 0.015 mol), and tetraethylene glycol (5.83 g, 0.03 mol) using dibutyltin diacetate (5.0% w/w) as catalyst. The reaction was stirred under nitrogen atmosphere at 120– 130 °C for 2 h, followed by heating the contents to 200 °C for 30 min, and by continued heating at 200 °C under vacuum (<1 mmHg) for an additional 2 h. The crude product was dissolved in tetrahydrofuran and obtained by precipitation with hexane, followed by dialysis using a MWt cut off at 1000 Da for five days. The product poly(tetraethyleneoxy n-octoxy isophthalate) was obtained as white granules and its structure was confirmed from its 1 H-NMR, 13 C-NMR and FTIR spectra. Other poly(ethyleneoxy alkoxy isophthalate)s (16– 27) were synthesized in the same fashion as 22, the percentage isolated yields in all the cases were above 80% (Table 2).
3. Results and discussion 3.1. Synthesis The main motivation behind this work was to develop functional, safe and biodegradable amphiphilic polymers having the characteristics: (1) flexibility to change the size of hydrophilic and hydrophobic segments in the polymer,
Mv (g/mol)
as the right balancing of hydrophobic to hydrophilic segments in the repeating units may lead to lower CMCs, (2) the functional monomer should have sites so that it can be tailored under mild conditions, (3) the copolymers should be of sufficiently high molecular weight to allow them to have desirable physical properties. In accordance with these considerations, two new monomers, dimethyl 5-n-butoxy isophthalate (DMBI, 2) and dimethyl 5-n-octoxy isophthalate (DMOI, 3) were designed and synthesized by the alkylation of phenolic hydroxyl group of dimethyl 5-hydroxy isophthalate with n-butyl bromide (or n-octyl bromide) as outlined in Scheme 1. The structures and purities of these compounds were confirmed by their spectral studies. The functionalized monomers 2 and 3 were used for the synthesis of poly(ethyleneoxy alkoxy isophthalates) (16–27) via a two-step sequence, i.e. transesterification and polycondensation with PEGs 4–9 by using dibutyltin diacetate as catalyst (Scheme 2). The transesterification was accomplished by converting the methoxy group of diesters with PEGs at temperatures of 120–130 °C. The post-condensation step was then performed at a temperature of 200 °C under vacuum in order to get polyesters of higher molecular weight. No traces of unreacted isophthalates were observed in the polymers. All the synthesized polymers were soluble in water and were easily purified by dissolving in water and filtering off
K. Danprasert et al. / European Polymer Journal 39 (2003) 1983–1990 O
1987 O
O
O
4 H3 CO
OCH3
H3CO
RBr, K2CO3
OCH3 6
DMF, 80oC
2 1 O
OH
7 8
2. R=10 CH3 3. R=10 CH211CH212CH213CH214CH3
9 R
Scheme 1. Synthetic route of dimethyl 5-alkoxy isophthalates.
O
O O
H3CO
OC H3
R
H
HO
+
n O
4. 5. 6. 7. 8. 9.
Dibutyltin diacetate 20 0 o C, vacuum
n= 3 n= 5 n= 8 n= 13 n= 19 n= 33
1. R =H 2. R =O-nButyl 3. R= O-nOc tyl
O
O
4
7
10
O O
8
9
H n
O
2
6
x R 10. 11. 12. 13. 14. 15.
R=H, n=3 R=H, n=5 R=H, n=8 R=H, n=13 R=H, n=19 R=H, n=33
16. 17. 18. 19. 20. 21 .
R=O-nBut, n= 3 R=O-nBut, n= 5 R=O-nBut, n= 8 R=O-nBut, n= 13 R=O-nBut, n= 19 R=O-nBut, n= 33
22. R= O-nOc t, n=3 23 . R=O-nOc t, n= 5 24 . R=O-nOc t, n= 8 25 . R=O-nOc t, n= 13 26 . R=O-nOc t, n= 19 27 . R=O-nOc t, n= 33
Scheme 2. Polymerization reactions.
any unreacted isophthalate derivatives (the latter are not soluble in water). After purification, all polyesters were obtained in yields of 80% or more and were characterized by one- and two-dimensional NMR and FTIR spectroscopy.
3.2. Characterization The structures of the repeating units of the polymers were identified from their 1 H (1D and 2D) and 13 C-NMR spectral data. DEPT-45, DEPT-90, and
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K. Danprasert et al. / European Polymer Journal 39 (2003) 1983–1990
Intrinsic viscosity (dl/g)
DEPT-135 were performed to characterize the carbon signals in the polymer structures. In the 1 H-NMR spectrum of poly(ethyleneoxy-1500 n-octoxy isophthalate) (27), the appearance of signal around d 4.50 for two protons indicated the formation of the ester linkages in the polymer; this was further confirmed by the muchdecreased intensity of the signal due to the methoxy protons of the dimethyl 5-octoxy isophthalate (3). In the 1 H–1 H-correlation spectrum, the signal around d 4.50 showed coupling with signal around d 3.9, i.e. the bproton of the PEG end group involved in linkage to the aromatic moiety. The signal at d 4.1 showed coupling with the signal at d 1.90 and was assigned to the OCH2 and OCH2 CH2 , respectively of the n-octoxy chain. The aromatic protons appeared as two broad singlets at d 8.28 (integrating for one proton) and at d 7.76 (integrating for two protons), whereas a broad peak in the region d 3.6–3.7 was due to the PEG main chain protons. The 13 C-NMR spectrum of copolymer 27 showed a signal at d 165.0 and was assigned to the carbonyl carbon of the newly formed ester moiety, by comparison with the signal for carbonyl group of methyl ester in the monomer at d 167.0. In order to study the effect of PEG main chain and side chains on the molecular weights of the polymers, a series of different polyesters were synthesized as summarized in Table 1 and Table 2. Viscosity molecular weights ðMv Þ of polyesters were determined by the Mark–Houwink–Sakurada relationship: ½g ¼ KMva . The K-value and a-value to calculate the molecular weights of the polymers were 2.37 104 (dl/g) and 0.73, as obtained from the polyethylene terephthalate (PET) model [15]. The experiments showed that polymers, synthesized from polycondensation between diesters 1–3 and PEGs 4–9, gave different degrees of polymerization (DPs). Polyesters 10–15 obtained by the polycondensation reaction of 1 with 4–9 have higher DPs (20–27, Table 1) than the copolymers 16–21 (DPs ¼ 10–15,
Table 2) obtained by the polycondensation of 2 with 4–9. The polyesters 22–27 obtained by the polycondensation of 3 with 4–9 resulted in still lower degree of polymerization, i.e. DPs ¼ 8–11 (Table 2). These observations indicated that the alkyl chains of diesters influenced the degree of polymerization. The lower DP values of 16–27 than those of 10–15 are attributed to the bulkier alkyl chains in the former copolymers, which inhibited the extent of polymerization. In a dilute polymer solution regime, association forces were mostly of an intramolecular nature since individual chains were farther apart from each other. The solution behaviors of single polymer chains were studied under two factors, the pendant group effect (due to the alkyl chain in diesters) and the polymer backbone length effects (due to the different sized PEG units). 3.3. Effect of polymer backbone length In the polyesters composed of diesters 1–3 and PEGs, the number of repeating units of polymer was in proportion to the molecular weights of PEGs. The higher molecular weight PEG chains gave longer polymer chains. According to FloryÕs equation ½g ¼ u½ðr2 Þ1=2 3 = M, where u is a universal constant, ½ðr2 Þ1=2 3 is the cube of a linear dimension of random coil chain and M is molecular weight of polymer [16], intrinsic viscosity increased with the length of polymer chain. To confirm this assumption, a study of the effect of molecular weights of PEGs on intrinsic viscosities of the polymers was conducted in three groups, i.e. 10–15 (composing of 1 and 4–9), 16–21 (having 2 and 4–9) and 22–27 (composing of 3 and 4–9) systems. The study of polyesters 10–15 accordingly showed that the viscosities increased with molecular weights of PEGs (Fig. 1). The same phenomena were observed in polyester systems 16–21 and 22–27. The explanation of this solution behavior could be attributed to a hydrodynamic volume effect.
0.5 0.45 0.4 0.35 0.3 0.25 0.2 0.15 0.1 0.05 0 0
500 Poly(ethyleneisophthalate)s Poly(ethylene butoxyisophthalate)s Poly(ethylene octoxyisophthalate)s
1000
1500
Mwt of PEG
Fig. 1. Effect of polymer backbone on intrinsic viscosity.
The longer polymer backbone chains, resulting from higher molecular weight PEGs, occupied more hydrodynamic volume leading to higher intrinsic viscosities. 3.4. Effect of pendant groups The effects of alkyl chains in pendant groups on viscosities were also determined. The overall analysis demonstrated that intrinsic viscosities of polymers derived from the same PEG and different diesters are different. Thus copolymers of dimethyl isophthalate (1) had higher viscosities than those derived from dimethyl 5-n-butoxy isophthalate (2) and dimethyl 5-n-octoxy isophthalate (3), this is because the polymer with dimethyl isophthalate has higher degree of polymerization. However, polymers having the same range of degree of polymerization (16, 17, 22 and 23) with DP values of 9– 11 were selected to study pendant group effects on polymer solution viscosities. The experiments show that these four polymers had similar values of viscosities (Table 2). This behavior indicated that the effect of the pendant chain on the polymer viscosities is not very significant. This is because these polymer systems have dangling chains, shorter than the backbone chain, and thus have no significant contribution to their hydrodynamic volume. The intrinsic viscosities of these polyesters appear to be affected more by polymer backbone length (contributed by the PEG moieties) than by the pendant groups in the aromatic diester moieties. 3.5. Critical micelle concentrations These amphiphilic polyesters associate through an entropy driven process of hydrophobic interactions to form micelles at critical concentration. An estimate for change in standard free energy of micellization, DG0 , by closed association was given by DG0 ¼ RT lnðCMCÞ where R is the gas constant, and T is the absolute temperature. CMCs for block copolymers that contain PEO, such as poly(ethylene oxide) copolymers with polystyrene (PEO–Psty) and poly(ethylene oxide) copolymers with poly(b-benzyl-L -aspartate), (PEO–PBLA) are of the order of 106 –107 M [17,18], whereas the CMCs for low molecular weight surfactants are of the order of 103 – 104 M [13]. To determine the CMCs of the polyesters 10–27, they were dissolved in deionized water in order to make eight different concentrations, viz. 0.15, 0.31, 0.62, 1.25, 2.50, 5.0, 10 and 20 mg/ml. The surface tensions of these solutions were measured by a tensiometer. As a representive case, Fig. 2 shows the relationship between surface tension and concentration of the solutions of the copolymer 27. The CMCs were obtained from the turning point of two different slopes, and are summarized in Tables 1 and 2. It was found that CMC of the polymer
Surface Tension (dynes/cm)
K. Danprasert et al. / European Polymer Journal 39 (2003) 1983–1990
1989
55 50 45 40 35 0
5
10
15
20
25
Concentration (mg/ml)
Fig. 2. The relationship between polymer concentration and surface tension of poly(ethyleneoxy-1500 n-octoxy isophthalate) (27) solution in distilled water.
decreases with the increasing molecular weight, which is in agreement with the literature reports. These phenomena illustrated that a higher thermodynamic tendency of micelle formation takes place at lower CMC of polymer having higher molecular weight.
4. Conclusions In the present study, copolymers, poly(ethyleneoxy alkoxy isophthalate)s and poly(ethyleneoxy isophthalate)s were synthesized using dibutyltin diacetate as catalyst. Poly(ethyleneoxy alkoxy isophthalate)s having hydrophobic side chains and hydrophilic main PEG chains were studied for their micelle forming abilities. It has been observed that by changing the amount of hydrophilic segments of PEGs and hydrophobic segments of diesters, the copolymers provide different chain structures and different micelle-forming characters. The molecular weights (Mv ) of the polymers formed are dependent on the sizes of both the side chain as well as of the PEG segment. The solution behavior, such as aggregation, deseggregation and inter-molecular and intra-molecular interactions of polymer chains of these polyesters and the shapes of micelles along with the studies to evaluate their potential as drug delivery vehicles for hydrophobic drugs are currently underway in our laboratories and will be the subject of subsequent publications.
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[5] Cecchi R, Rusconi L, Tanzi MC, Danusso F. J Med Chem 1981;24:622. [6] Zunino F, Pratesi G, Micheloni A. J Controlled Release 1989;10:65. [7] Abuchowski A, Davis FF. In: Holsenburg J, Roberts J, editors. Enzymes as drugs. New York: Wiley; 1981. p. 367. [8] (a) Cameron NS, Corbierre MK, Eisenberg A. Can J Chem 1999;77:1311; (b) Gref R, Minamitake Y, Peracchia MT, Trubestskoy V, Torcchilin V, Langer R. Science 1994;263:1600; (c) Xu R, Winnik A, Hallett FR, Riess G, Croucher MD. Macromolecules 1991;24:87; (d) Kataoka K, Kwon GS, Yokoyama M, Okano T, Sakurai Y. J Controlled Release 1993;24:119. [9] Kwon GS, Suwa S, Yokoyama M, Okana T, Sakurai Y, Kataoka K. J Controlled Release 1994;29:17.
[10] Gao Z, Varshney SK, Wong S, Eisenberg A. Macromolecules 1994;27:7923. [11] Yu K, Eisenberg A. Macromolecules 1996;29:6359. [12] Kwon GS, Naito M, Okano T. Colloid Surf, B: Biointerfaces 1994;2:429. [13] Kwon GS, Kazunori K. Adv Drug Deliver Rev 1995;16: 295. [14] Piskin E, Kaitian X, Kucukyavuz Z. J Biomater Sci Polym Edn 1995;7:395. [15] Karagannidis GP, Kokkalas DE, Bikiaris DN. J Appl Polym Sci 1993;50:2135. [16] Billmeyer FW. Textbook of polymer science. 3rd ed. John Wiley and Sons; 1994. p. 212. [17] Kwon GS, Naito M, Yokoyama M, Okano T, Sakurai Y, Kataoka K. Langmuir 1993;9:945. [18] Zhao C, Winnik MA, Riess G, Croucher MD. Langmuir 1990;6:514.
Synthesis of novel poly(ethylene glycol) based amphiphilic polymers Kunya Danprasert a, Rajesh Kumar a,b, Ming H-Cheng a, Pankaj Gupta c, Najam A. Shakil a,c, Ashok K. Prasad c, Virinder S. Parmar a,c, Jayant Kumar b, Lynne A. Samuelson d, Arthur C. Watterson a,* a
d
Department of Chemistry, Institute for Nano Science and Engineering Technology, University of Massachusetts, Lowell, MA 01854, USA b Center for Advanced Materials, Department of Chemistry, University of Massachusetts, Lowell, MA 01854, USA c Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India Natick Soldier Center, US Army Soldier and Biological Chemical Command, Kansas Street, Natick, MA 01760, USA Received 6 March 2003; received in revised form 16 May 2003; accepted 16 May 2003
Abstract The synthesis of new amphiphilic polyesters based on poly(ethylene glycol) (PEGs) and studies on their solution properties are reported. Two novel monomers, dimethyl 5-n-butoxy isophthalate (2) and dimethyl 5-n-octoxy isophthalate (3) were synthesized. Three series of novel amphiphilic polyesters, i.e. poly(ethyleneoxy isophthalate)s (10–15), poly(ethyleneoxy n-butoxy isophthalate)s (16–21) and poly(ethyleneoxy n-octoxy isophthalate)s (22–27) have been synthesized from PEGs of different sizes and dimethyl isophthalates 1–3 via the transesterification–polycondensation using dibutyltin diacetate as a catalyst. The structures of the polyesters were established from a detailed analysis of their spectra, i.e. FTIR, 1 H-NMR (one- and two-dimensional) and 13 C-NMR. By adjusting the ratio of hydrophobic (diesters) and hydrophilic (PEGs) segments in polymers, their main chain structures and solution properties could be changed. The viscosity molecular weights (Mv ) of polymers, obtained from Mark–Houwink–Sakurada relationship having poly(ethylene terephthalate) as a model, were in the range of 4500–32,000 g/mol. Intrinsic viscosities were studied based on polymer backbone length (PEGs effect) and pendant group (diesters effect) and these were found to be dependent on molecular weights of the PEGs used. Ó 2003 Elsevier Ltd. All rights reserved.
1. Introduction The unique properties of poly(ethylene glycol) (PEG), including a wide range of solubility, lack of toxicity, absence of antigenicity and immunogenicity, non-interference with enzymatic activities and conformations of polypeptides, and ease of excretion from living organisms, make them ideal drug carriers [1,2]. The
* Corresponding author. Tel.: +1-978-934-3691; fax: +1-978458-9571. E-mail address: [email protected] (A.C. Watterson).
two-hydroxyl end groups of PEG have been suitably functionalized prior to coupling [3] with ligands of biological relevance, although the hydroxyl groups themselves have been used as well [4–7]. Because the number of terminal groups of PEGs (only two) to attach with drugs limits their drug loading capacity, extensive work has been done to functionalize them by copolymerizing PEGs with various functional monomers. Amphiphilic block copolymers with hydrophilic and hydrophobic segments have been investigated extensively not only because of their unique self-organization characteristics but also for their wide range of potential applications, such as in drug delivery and separation technology systems [8]. The micellar characteristics of
0014-3057/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0014-3057(03)00111-3
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K. Danprasert et al. / European Polymer Journal 39 (2003) 1983–1990
amphiphilic diblock copolymers depend on the nature of each block and the surface properties of self-organized micelles are highly dependent on the structures of the hydrophilic blocks [9–11]. Kwon et al. [12,13] synthesized AB block copolymers of poly(ethylene oxide) (PEO) and poly(b-benzyl-L aspartate) (PBLA). The distribution of hydrophobic moieties into the PEO–PBLA micelles was investigated by UV spectroscopy using pyrene as a model. Recent efforts in the design of drug delivery systems have led to the development of vehicles that circulate for prolonged periods in the vascular system. A common feature of the new drug vehicles is PEO at their surfaces. PEO is a nontoxic, highly hydrating polymer (through hydrogen bonding) that sterically stabilizes surfaces in aqueous systems, and this is effective for preventing the adsorption of proteins and adhesion of cells [14]. In this work, we report the synthesis of new class of amphiphilic copolymers by transesterification–polycondensation of hydrophilic PEGs and hydrophobic functionalized dimethyl 5-hydroxy isophthalate monomers and their solution properties. The polymeric system and design described in this paper are very unique and highly flexible as compared to already reported PEG based systems. Most of the PEG modified systems are diblock polymeric systems. The flexibility in adjusting the ratio of hydrophilic segments (PEGs) and hydrophobic segments (modified diester compounds) provides easy access to tailor the polymer solution properties. PEGs of different sizes were used for the polymerization as well as three different sets of hydrophobic monomers were used. The critical micelle concentration (CMCs) values of polymers have been investigated and determined by surface tension measurements. Intrinsic viscosities were studied based on polymer backbone length (PEGs effect) and nature of the pendant group (diesters effect) and these were found to be dependent on molecular weights of the PEGs.
2. Experimental
concentration used was 4% w/v in chloroform-d. Carbon-13 (13 C)-NMR spectra were recorded at 62.5 MHz on a Bruker spectrometer in 20% w/v chloroform-d solutions. The chemical shifts in ppm are referenced relative to the internal standard chloroform-d at 77.00 ppm. 2.3. Infrared spectroscopy A Perkin-Elmer 1760 FTIR spectrometer was used to obtain the spectra after 32 scans (8 cm1 resolution) over the range 4000–400 cm1 . Liquid films on a NaCl pellet and potassium bromide pellets were used for sample preparation. 2.4. UV–visible spectroscopy A UV–visible 916, GBC Scientific equipment, with double beams and direct ratio recording system was used to determine absorbance of samples. The spectrometer was equipped with 50 W tungsten–halogen and 30 W deuterium lamps and a silicone photodiode detector. 2.5. Solution properties Viscosities were investigated to study polymer solution properties. All polymer viscosities were determined under semi-concentration (5.0% w/v) and dilute concentration (0.1% w/v) using water as a media. The viscosity shear rate relationships of the polymers were measured by a Wells–Brookfield cone and plate model HATDCP digital viscometer having 0.8° cone and 0.5 ml sample size at 25 °C. Dilute solution viscosity (intrinsic viscosity) measurements were obtained by an Ubbelohde dilution viscometer maintained in a water bath at a constant temperature of 25.0 0.1 °C. 2.6. Surface tension measurements All polymer solutions were prepared in distilled water and the CMCs were determined using a Fisher Scientific Surface Tensiomat 21.
2.1. Materials All the chemicals and solvents were purchased from Aldrich Chemical Co. and used as received unless otherwise specified. PEGs and monomers were dried in a vacuum oven overnight before use. 2.2. Nuclear magnetic resonance spectroscopy (NMR) Proton (1 H)-NMR spectra were recorded on a Bruker spectrometer at 250 MHz. The chemical shifts in parts per million (ppm) are reported downfield from 0.00 ppm using tetramethylsilane as an internal reference. The
2.7. Synthesis of dimethyl 5-n-octoxy isophthalate (3) To a solution of dimethyl 5-hydroxy isophthalate (5.0 g, 23.8 mmol) in DMF (200 ml) was added fused potassium carbonate (6.5 g, 47.2 mmol) and the contents stirred for 1 h at 80 °C under nitrogen atmosphere. To this mixture, a solution of 1-bromooctane (4.6 g, 23.8 mmol) in DMF (50 ml) was added and the mixture was allowed to stir for 6 h and the progress of reaction was monitored by thin layer chromatography using a solvent system of ethyl acetate and hexane. After completion, the solvent was removed under reduced pressure on a
K. Danprasert et al. / European Polymer Journal 39 (2003) 1983–1990
1985
It was also synthesized as a white solid as described above. 1 H-NMR (CDCl3 ): d 0.95 (3H, C-10H), 1.55 (2H, C9H), 1.83 (2H, C-8H), 3.95 (6H, 2 OCH3 ), 4.08 (2H, C-7H), 7.70 (2H, C-2H and C-6H) and 8.25 (1H, C-4H). 13 C-NMR (CDCl3 ): d 14.07 (C-10), 19.52 (C-9), 31.51 (C-8), 52.63 (OCH3 ), 68.74 (C-7), 120.25 (C-2 and C-6), 123.13 (C-4), 132.14 (C-3 and C-5), 159.67 (C-1) and 166.55 (COO). FTIR (cm1 ): 2956, 2875, 1728 (COO), 1595, 1457, 1435, 1340, 1242, 1117, 1036 and 758.
butyltin diacetate (as catalyst, 5.0% w/w) was stirred at 120–130 °C for 2 h under nitrogen atmosphere. The mixture was then heated to 200 °C and allowed to react at this temperature for 30 min, the reaction was continued under reduced pressure (less than 1 mmHg) for an additional 2 h. The crude product was dissolved in tetrahydrofuran and precipitated with hexane, the precipitate so obtained was redissolved in water to remove any traces of unreacted isophthalates (as these are not water soluble) and then placed in a dialysis bag having a MWt cut off at 1000 Da. The final product [poly(tetraethyleneoxy isophthalate), 10] was obtained as a viscous oil. 1 H-NMR (CDCl3 ): d 3.60–3.70 (m, C-9H and C10H), 3.90 (t, 2H, C-8H), 4.50 (t, 2H, C-7H), 7.55 (t, 1H, C-1H), 8.25 (d, 2H, H-2 and H-6) and 8.70 (s, 1H, C4H). 13 C-NMR (CDCl3 ): d 62.38 (C-10), 62.44 (C-9), 64.41 (C-8), 71.40 (C-7), 130.0 (C-1, C-2 and C-6), 132.0 (C-3 and C-5), 136.0 (C-4) and 168.0 (COO). FTIR (cm1 ): 3495 (OH), 2872, 1724 (COO), 1609, 1455, 1355, 1304, 1235, 1127, 937, 868, 732 and 519. Other poly(ethyleneoxy isophthalate)s synthesized were poly(hexaethyleneoxy isophthalate) (11), poly(ethyleneoxy-400 isophthalate) (12), poly(ethyleneoxy-600 isophthalate) (13), poly(ethyleneoxy-900 isophthalate) (14) and poly(ethyleneoxy-1500 isophthalate) (15) by the polycondensation of dimethyl isophthalate and the corresponding PEGs of different molecular weights by the above mentioned procedure, the isolated yields in all these reactions were around 80% (Table 1).
2.9. Synthesis of poly(tetraethyleneoxy isophthalate) (10)
2.10. Synthesis of poly(ethyleneoxy n-alkoxy isophthalate)s (16–27)
A mixture of dimethyl isophthalate (1, 2.90 g, 0.015 mol), tetraethylene glycol (5.83 g, 0.03 mol) and di-
Synthesis of poly(tetraethyleneoxy n-octoxy isophthalate), 22: This was synthesized via transesterification
vacuum rotavapor, followed by the addition of water. The product was extracted with CH2 Cl2 . The organic layer was collected and dried over anhydrous magnesium sulfate. The solvent was then removed to give a white solid powder, which recrystallized from methanol to give a white crystalline solid. 1 H-NMR (CDCl3 ): d 0.89 (3H, C-14H), 1.20–1.35 (10H, C-9H to C-13H), 1.85 (2H, C-8H), 3.95 (6H, 2 OCH3 ), 4.13 (2H, C-7H), 7.76 (2H, C-2H and C-6H) and 8.20 (1H, C-4H). 13 C-NMR (CDCl3 ): d 14.35 (C-14), 22.96 (C-12 and C-13), 26.32 (C-10 and C-11), 29.46 (C-9), 32.13 (C-8), 52.62 (OCH3 ), 69.06 (C-7), 120.25 (C-2 and C-6), 123.13 (C-4), 132.15 (C-3 and C-5), 159.67 (C-1) and 166.54 (COO). FTIR (cm1 ): 2928, 2857, 1729 (COO), 1595, 1456, 1435, 1340, 1314, 1241, 1118, 1104, 1049, 1006 and 759. 2.8. Synthesis of dimethyl 5-n-butoxy isophthalate (2)
Table 1 Effect of PEG chain length on the Mv , CMC and DP of poly(ethyleneoxy isophthalate)s Monomer (diester)
Poly(ethylene glycol)
Polyester
Avg [g] (dl/g)
DP (avg)
CMC (mmol)
Dimethyl isophthalate (1)
Tetraethylene glycol (4)
Poly(tetraethyleneoxy isophthalate) (10) Poly(hexaethyleneoxy isophthalate) (11) Poly(ethyleneoxy-400 isophthalate) (12) Poly(ethyleneoxy-600 isophthalate) (13) Poly(ethyleneoxy-900 isophthalate) (14) Poly(ethyleneoxy-1500 isophthalate) (15)
0.1652
24
–
7800
0.1935
24
0.31
9700
0.2197
22
0.50
12,000
0.3259
27
0.31
19,900
0.3393
20
0.34
21,000
0.4604
20
0.25
32,000
Hexaethylene glycol (5) Poly(ethylene glycol)-400 (6) Poly(ethylene glycol)-600 (7) Poly(ethylene glycol)-900 (8) Poly(ethylene glycol)-1500 (9)
Mv (g/mol)
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Table 2 Effect of PEG chain length on the Mv , CMC and DP of poly(ethyleneoxy alkoxy isophthalate)s Monomer (diester)
PEG
Polyester
Avg [g] (dl/g)
DP (avg)
CMC (mmol)
Dimethyl 5-n-butoxy isophthalate (2)
Tetraethylene glycol (4)
Poly(tetraethyleneoxy butoxy isophthalate) (16) Poly(hexaethyleneoxy butoxy isophthalate) (17) Poly(ethyleneoxy-400 butoxy isophthalate) (18) Poly(ethyleneoxy-600 butoxy isophthalate) (19) Poly(ethyleneoxy-900 butoxy isophthalate) (20) Poly(ethyleneoxy-1500 butoxy isophthalate) (21)
0.1096
11
–
4500
0.1178
10
2.53
4900
0.1672
13
0.81
8000
0.2130
14
0.68
11,000
0.2842
15
0.59
16,000
0.3610
14
0.31
24,000
Poly(tetraethyleneoxy octoxy isophthalate) (22) Poly(hexaethyleneoxy octoxy isophthalate) (23) Poly(ethyleneoxy-400 octoxy isophthalate) (24) Poly(ethyleneoxy-600 octoxy isophthalate) (25) Poly(ethyleneoxy-900 octoxy isophthalate) (26) Poly(ethyleneoxy-1500 octoxy isophthalate) (27)
0.1152
11
–
4800
0.1114
9
1.35
4600
0.1494
10
0.96
6800
0.1854
11
0.70
9100
0.1794
8
0.78
8800
0.2984
10
0.39
18,000
Hexaethylene glycol (5) Poly(ethylene (6) Poly(ethylene (7) Poly(ethylene (8) Poly(ethylene (9)
Dimethyl 5-n-octoxy isophthalate (3)
glycol)-400 glycol)-600 glycol)-900 glycol)-1500
Tetraethylene glycol(4) Hexaethylene glycol (5) Poly(ethylene (6) Poly(ethylene (7) Poly(ethylene (8) Poly(ethylene (9)
glycol)-400 glycol)-600 glycol)-900 glycol)-1500
between dimethyl 5-n-octoxy isophthalate (3, 4.83 g, 0.015 mol), and tetraethylene glycol (5.83 g, 0.03 mol) using dibutyltin diacetate (5.0% w/w) as catalyst. The reaction was stirred under nitrogen atmosphere at 120– 130 °C for 2 h, followed by heating the contents to 200 °C for 30 min, and by continued heating at 200 °C under vacuum (<1 mmHg) for an additional 2 h. The crude product was dissolved in tetrahydrofuran and obtained by precipitation with hexane, followed by dialysis using a MWt cut off at 1000 Da for five days. The product poly(tetraethyleneoxy n-octoxy isophthalate) was obtained as white granules and its structure was confirmed from its 1 H-NMR, 13 C-NMR and FTIR spectra. Other poly(ethyleneoxy alkoxy isophthalate)s (16– 27) were synthesized in the same fashion as 22, the percentage isolated yields in all the cases were above 80% (Table 2).
3. Results and discussion 3.1. Synthesis The main motivation behind this work was to develop functional, safe and biodegradable amphiphilic polymers having the characteristics: (1) flexibility to change the size of hydrophilic and hydrophobic segments in the polymer,
Mv (g/mol)
as the right balancing of hydrophobic to hydrophilic segments in the repeating units may lead to lower CMCs, (2) the functional monomer should have sites so that it can be tailored under mild conditions, (3) the copolymers should be of sufficiently high molecular weight to allow them to have desirable physical properties. In accordance with these considerations, two new monomers, dimethyl 5-n-butoxy isophthalate (DMBI, 2) and dimethyl 5-n-octoxy isophthalate (DMOI, 3) were designed and synthesized by the alkylation of phenolic hydroxyl group of dimethyl 5-hydroxy isophthalate with n-butyl bromide (or n-octyl bromide) as outlined in Scheme 1. The structures and purities of these compounds were confirmed by their spectral studies. The functionalized monomers 2 and 3 were used for the synthesis of poly(ethyleneoxy alkoxy isophthalates) (16–27) via a two-step sequence, i.e. transesterification and polycondensation with PEGs 4–9 by using dibutyltin diacetate as catalyst (Scheme 2). The transesterification was accomplished by converting the methoxy group of diesters with PEGs at temperatures of 120–130 °C. The post-condensation step was then performed at a temperature of 200 °C under vacuum in order to get polyesters of higher molecular weight. No traces of unreacted isophthalates were observed in the polymers. All the synthesized polymers were soluble in water and were easily purified by dissolving in water and filtering off
K. Danprasert et al. / European Polymer Journal 39 (2003) 1983–1990 O
1987 O
O
O
4 H3 CO
OCH3
H3CO
RBr, K2CO3
OCH3 6
DMF, 80oC
2 1 O
OH
7 8
2. R=10 CH3 3. R=10 CH211CH212CH213CH214CH3
9 R
Scheme 1. Synthetic route of dimethyl 5-alkoxy isophthalates.
O
O O
H3CO
OC H3
R
H
HO
+
n O
4. 5. 6. 7. 8. 9.
Dibutyltin diacetate 20 0 o C, vacuum
n= 3 n= 5 n= 8 n= 13 n= 19 n= 33
1. R =H 2. R =O-nButyl 3. R= O-nOc tyl
O
O
4
7
10
O O
8
9
H n
O
2
6
x R 10. 11. 12. 13. 14. 15.
R=H, n=3 R=H, n=5 R=H, n=8 R=H, n=13 R=H, n=19 R=H, n=33
16. 17. 18. 19. 20. 21 .
R=O-nBut, n= 3 R=O-nBut, n= 5 R=O-nBut, n= 8 R=O-nBut, n= 13 R=O-nBut, n= 19 R=O-nBut, n= 33
22. R= O-nOc t, n=3 23 . R=O-nOc t, n= 5 24 . R=O-nOc t, n= 8 25 . R=O-nOc t, n= 13 26 . R=O-nOc t, n= 19 27 . R=O-nOc t, n= 33
Scheme 2. Polymerization reactions.
any unreacted isophthalate derivatives (the latter are not soluble in water). After purification, all polyesters were obtained in yields of 80% or more and were characterized by one- and two-dimensional NMR and FTIR spectroscopy.
3.2. Characterization The structures of the repeating units of the polymers were identified from their 1 H (1D and 2D) and 13 C-NMR spectral data. DEPT-45, DEPT-90, and
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K. Danprasert et al. / European Polymer Journal 39 (2003) 1983–1990
Intrinsic viscosity (dl/g)
DEPT-135 were performed to characterize the carbon signals in the polymer structures. In the 1 H-NMR spectrum of poly(ethyleneoxy-1500 n-octoxy isophthalate) (27), the appearance of signal around d 4.50 for two protons indicated the formation of the ester linkages in the polymer; this was further confirmed by the muchdecreased intensity of the signal due to the methoxy protons of the dimethyl 5-octoxy isophthalate (3). In the 1 H–1 H-correlation spectrum, the signal around d 4.50 showed coupling with signal around d 3.9, i.e. the bproton of the PEG end group involved in linkage to the aromatic moiety. The signal at d 4.1 showed coupling with the signal at d 1.90 and was assigned to the OCH2 and OCH2 CH2 , respectively of the n-octoxy chain. The aromatic protons appeared as two broad singlets at d 8.28 (integrating for one proton) and at d 7.76 (integrating for two protons), whereas a broad peak in the region d 3.6–3.7 was due to the PEG main chain protons. The 13 C-NMR spectrum of copolymer 27 showed a signal at d 165.0 and was assigned to the carbonyl carbon of the newly formed ester moiety, by comparison with the signal for carbonyl group of methyl ester in the monomer at d 167.0. In order to study the effect of PEG main chain and side chains on the molecular weights of the polymers, a series of different polyesters were synthesized as summarized in Table 1 and Table 2. Viscosity molecular weights ðMv Þ of polyesters were determined by the Mark–Houwink–Sakurada relationship: ½g ¼ KMva . The K-value and a-value to calculate the molecular weights of the polymers were 2.37 104 (dl/g) and 0.73, as obtained from the polyethylene terephthalate (PET) model [15]. The experiments showed that polymers, synthesized from polycondensation between diesters 1–3 and PEGs 4–9, gave different degrees of polymerization (DPs). Polyesters 10–15 obtained by the polycondensation reaction of 1 with 4–9 have higher DPs (20–27, Table 1) than the copolymers 16–21 (DPs ¼ 10–15,
Table 2) obtained by the polycondensation of 2 with 4–9. The polyesters 22–27 obtained by the polycondensation of 3 with 4–9 resulted in still lower degree of polymerization, i.e. DPs ¼ 8–11 (Table 2). These observations indicated that the alkyl chains of diesters influenced the degree of polymerization. The lower DP values of 16–27 than those of 10–15 are attributed to the bulkier alkyl chains in the former copolymers, which inhibited the extent of polymerization. In a dilute polymer solution regime, association forces were mostly of an intramolecular nature since individual chains were farther apart from each other. The solution behaviors of single polymer chains were studied under two factors, the pendant group effect (due to the alkyl chain in diesters) and the polymer backbone length effects (due to the different sized PEG units). 3.3. Effect of polymer backbone length In the polyesters composed of diesters 1–3 and PEGs, the number of repeating units of polymer was in proportion to the molecular weights of PEGs. The higher molecular weight PEG chains gave longer polymer chains. According to FloryÕs equation ½g ¼ u½ðr2 Þ1=2 3 = M, where u is a universal constant, ½ðr2 Þ1=2 3 is the cube of a linear dimension of random coil chain and M is molecular weight of polymer [16], intrinsic viscosity increased with the length of polymer chain. To confirm this assumption, a study of the effect of molecular weights of PEGs on intrinsic viscosities of the polymers was conducted in three groups, i.e. 10–15 (composing of 1 and 4–9), 16–21 (having 2 and 4–9) and 22–27 (composing of 3 and 4–9) systems. The study of polyesters 10–15 accordingly showed that the viscosities increased with molecular weights of PEGs (Fig. 1). The same phenomena were observed in polyester systems 16–21 and 22–27. The explanation of this solution behavior could be attributed to a hydrodynamic volume effect.
0.5 0.45 0.4 0.35 0.3 0.25 0.2 0.15 0.1 0.05 0 0
500 Poly(ethyleneisophthalate)s Poly(ethylene butoxyisophthalate)s Poly(ethylene octoxyisophthalate)s
1000
1500
Mwt of PEG
Fig. 1. Effect of polymer backbone on intrinsic viscosity.
The longer polymer backbone chains, resulting from higher molecular weight PEGs, occupied more hydrodynamic volume leading to higher intrinsic viscosities. 3.4. Effect of pendant groups The effects of alkyl chains in pendant groups on viscosities were also determined. The overall analysis demonstrated that intrinsic viscosities of polymers derived from the same PEG and different diesters are different. Thus copolymers of dimethyl isophthalate (1) had higher viscosities than those derived from dimethyl 5-n-butoxy isophthalate (2) and dimethyl 5-n-octoxy isophthalate (3), this is because the polymer with dimethyl isophthalate has higher degree of polymerization. However, polymers having the same range of degree of polymerization (16, 17, 22 and 23) with DP values of 9– 11 were selected to study pendant group effects on polymer solution viscosities. The experiments show that these four polymers had similar values of viscosities (Table 2). This behavior indicated that the effect of the pendant chain on the polymer viscosities is not very significant. This is because these polymer systems have dangling chains, shorter than the backbone chain, and thus have no significant contribution to their hydrodynamic volume. The intrinsic viscosities of these polyesters appear to be affected more by polymer backbone length (contributed by the PEG moieties) than by the pendant groups in the aromatic diester moieties. 3.5. Critical micelle concentrations These amphiphilic polyesters associate through an entropy driven process of hydrophobic interactions to form micelles at critical concentration. An estimate for change in standard free energy of micellization, DG0 , by closed association was given by DG0 ¼ RT lnðCMCÞ where R is the gas constant, and T is the absolute temperature. CMCs for block copolymers that contain PEO, such as poly(ethylene oxide) copolymers with polystyrene (PEO–Psty) and poly(ethylene oxide) copolymers with poly(b-benzyl-L -aspartate), (PEO–PBLA) are of the order of 106 –107 M [17,18], whereas the CMCs for low molecular weight surfactants are of the order of 103 – 104 M [13]. To determine the CMCs of the polyesters 10–27, they were dissolved in deionized water in order to make eight different concentrations, viz. 0.15, 0.31, 0.62, 1.25, 2.50, 5.0, 10 and 20 mg/ml. The surface tensions of these solutions were measured by a tensiometer. As a representive case, Fig. 2 shows the relationship between surface tension and concentration of the solutions of the copolymer 27. The CMCs were obtained from the turning point of two different slopes, and are summarized in Tables 1 and 2. It was found that CMC of the polymer
Surface Tension (dynes/cm)
K. Danprasert et al. / European Polymer Journal 39 (2003) 1983–1990
1989
55 50 45 40 35 0
5
10
15
20
25
Concentration (mg/ml)
Fig. 2. The relationship between polymer concentration and surface tension of poly(ethyleneoxy-1500 n-octoxy isophthalate) (27) solution in distilled water.
decreases with the increasing molecular weight, which is in agreement with the literature reports. These phenomena illustrated that a higher thermodynamic tendency of micelle formation takes place at lower CMC of polymer having higher molecular weight.
4. Conclusions In the present study, copolymers, poly(ethyleneoxy alkoxy isophthalate)s and poly(ethyleneoxy isophthalate)s were synthesized using dibutyltin diacetate as catalyst. Poly(ethyleneoxy alkoxy isophthalate)s having hydrophobic side chains and hydrophilic main PEG chains were studied for their micelle forming abilities. It has been observed that by changing the amount of hydrophilic segments of PEGs and hydrophobic segments of diesters, the copolymers provide different chain structures and different micelle-forming characters. The molecular weights (Mv ) of the polymers formed are dependent on the sizes of both the side chain as well as of the PEG segment. The solution behavior, such as aggregation, deseggregation and inter-molecular and intra-molecular interactions of polymer chains of these polyesters and the shapes of micelles along with the studies to evaluate their potential as drug delivery vehicles for hydrophobic drugs are currently underway in our laboratories and will be the subject of subsequent publications.
References [1] Topchiyeva IN. Polym Sci USSR 1990;32:833. [2] Zalipsky S, Lee C. In: Harris JM, editor. Poly(ethylene glycol) chemistry: biotechnical and biomedical applications. New York: Plenum Press; 1992. p. 347. [3] Zalipsky S, Gilon C, Zilkha A. Eur Polym J 1983;19:1177. [4] Harris JM. J Macromol Sci, Rev Macromol Chem Phys 1985;C25:325.
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