Colloid Polym Sci (2010) 288:1151–1159
DOI 10.1007/s00396-010-2246-2
ORIGINAL CONTRIBUTION
Effects of precipitate agents on temperature-responsive
sol–gel transitions of PLGA–PEG–PLGA copolymers
in water
Lin Yu & Huan Zhang & Jiandong Ding
Received: 27 August 2009 / Revised: 11 April 2010 / Accepted: 12 May 2010 / Published online: 3 June 2010
# Springer-Verlag 2010
Abstract This paper reports the effects of precipitate
agents used in the collection of block copolymers composed of poly(lactic acid-co-glycolic acid) (PLGA) and
poly(ethylene glycol) (PEG) on their thermogelling aqueous behaviors. We synthesized PLGA–PEG–PLGA triblock
copolymers with a relatively wide distribution of molecular
weight (MW) and then separated the crude polymers via
three different precipitate agents (diethyl ether, hexane, or
methanol). The obtained products exhibited, however,
significantly different macroscopic states in water: some
were sols, some were precipitates, and some underwent
sol–gel transition upon heating. We found that by using
different precipitate agents, ingredients of different MW
were collected from the synthesized polymers, which
accounted for the different states of the separated products
in water. Our study strengthens the importance of an
appropriate precipitate agent and reveals the subtle balance
of hydrophobicity and hydrophilicity in this sort of
amphiphilic block copolymers.
Keywords Sol–gel transition . Intelligent hydrogel .
Physical gel . Precipitate agent effect . Injectable
biomaterial . Amphiphilic block copolymer
Introduction
Precipitate agents are frequently used in the separation of
crude polymers after synthesis. Diethyl ether, hexane, and
L. Yu : H. Zhang : J. D. Ding (*)
Key Laboratory of Molecular Engineering of Polymers of
Ministry of Education, Department of Macromolecular Science,
Advanced Materials Laboratory, Fudan University,
Shanghai 200433, China
e-mail: [email protected]
methanol are three of the most popular precipitate agents to
collect polymers after the crude polymers are dissolved in a
solvent [1–5], say, methylene chloride [3, 5, 6]. Usually, one
polymer could be collected by several precipitate agents [7–
13]. The present study demonstrates, however, that the
products separated via different precipitate agents might
exhibit significantly different physical behaviors. For the
block copolymer of poly(ethylene glycol) (PEG) and poly
(lactic acid-co-glycolic acid) (PLGA), we found that the
precipitate agents used in product collection could determine
the basic states of polymer–water mixtures: a sol, a physical
gel, or a precipitate. When only using an appropriate
precipitate agent, the PLGA–PEG–PLGA synthesized in this
study could undergo a thermoreversible sol–gel transition
upon heating and serve as an intelligent biomaterial.
In the latest decade, stimulus-responsive hydrogels and
their applications have been an issue of intensive research
[14–21]. In particular, biodegradable thermogelling polymers have, as an injectable hydrogel, widely been investigated due to their promising biomedical applications such
as drug delivery, tissue engineering, and wound healing
[22–28]. Drugs and cells could be simply mixed with the
aqueous copolymer solutions at low temperatures and, then
after injection into the body, efficiently encapsulated into a
semi-solid matrix because the solution is converted into a
physical hydrogel. Typical examples of thermosensitive
polymers include PEG/PLGA [7, 11, 29], PEG/poly(caprolactone) [9, 10], PEG/poly(propylene glycol)/polyester [6],
chitosan/glycerolphosphate [30], poly(phosphazenes) [31],
and poly(peptides) [32, 33]. Among biodegradable thermosensitive polymers, PLGA–PEG–PLGA triblock copolymer
hydrogel has been successfully used as controlled release
carriers of drug [34–37]. Its formulation with paclitaxel
(OncoGe™) is in clinical phase 2 [38, 39]. The degradation
rate, sol–gel transition temperature, critical gelation con-
1152
centration, and permeability of this kind of polymer
hydrogels can be adjusted by changing molecular weight
(MW) of polymers, block ratio, concentration, etc. [7, 35]
and can also be influenced by external additives such as
PEG homopolymers and salts [29, 40]. In a previous work,
we have found a significant end-group effect on macroscopic physical gelation of PLGA–PEG–PLGA triblock
copolymer aqueous solutions [41, 42], which reveals that
an end-capping approach can be adopted to tune the
gelation behaviors of thermosensitive polymers.
In this study, we report the significant effects of
precipitate agents used in collection of PLGA–PEG–PLGA
triblock copolymers on their thermogelling behaviors after
being dissolved in water. PLGA–PEG–PLGA triblock
copolymers with two mean MWs were synthesized. The
crude copolymers were separated via different precipitate
agents. The products exhibited, however, significantly
different aqueous behaviors. The underlying reason will
be preliminarily discussed, and the importance of a careful
selection of the product separation process will be demonstrated. Meanwhile, this study also gives more insight into
the relationship of the chemical component and physical
gelation of amphiphilic block copolymers.
Experimental
Materials
PEG (MW 1,000) and stannous 2-ethylhexanoate (stannous
octoate, 95%) were purchased from Sigma. DL-lactide (LA)
and glycolide (GA) were donated by Purac and used as
received. All other chemicals were of reagent grade and
used as received.
Synthesis of PLGA–PEG–PLGA and its separation
via precipitate agents
Colloid Polym Sci (2010) 288:1151–1159
heated to 80 °C to precipitate the polymer products and
remove water-soluble low-MW polymers and unreacted
monomers. The precipitated polymer was separated from the
supernatant by decantation. The above process was repeated
to obtain the copolymer, and the residual water in the
copolymer was removed by lyophilization. Copolymer-2
with just a different mean MW in this study was synthesized
by the same method.
The preliminarily separated copolymers were further
separated by being dissolved in dichloromethane (CH2Cl2)
and then precipitated in one of three precipitate agents,
diethyl ether, hexane, or methanol at −20 °C for several
days. Excess precipitate agents were used. The precipitated
products were decanted to an eggplant bottle by being
dissolved in dichloromethane and collected by the evaporation of solvent with a rotary evaporator. The products
were dried in vacuo at 60 °C for over 8 h and then at
ambient temperature for over 48 h.
Synthesis of PLGA
Some PLGA copolymers without the PEG block were also
prepared, following the similar method described by Li and
Kissel [44]. Briefly, 1,6-hexane diol, LA and GA were
added into a vigorously dried polymerization tube and dried
under vacuum at 120 °C for 2 h. At the end of 2 h, the
initiator, stannous octoate (0.2 wt.%) was added. Then, the
tube was sealed under vacuum. The sealed tube was
immersed and kept in a silicone oil bath at 160 °C for
12 h. The tube was subsequently broken, and the product
was isolated by being dissolved in dichloromethane and
then precipitated into an excess amount of a mixture solvent
of diethyl ether and hexane (ratio 1:1) twice. The residual
solvent was removed under vacuum.
Characterizations of chemical structures and MW
1
Triblock copolymers PLGA–PEG–PLGA were prepared
based on our previous work [37, 43]. The synthesis of
copolymer-1 was as follows: firstly, PEG (10 g) was dried in
a three-necked flask by stirring under vacuum at 150 °C for
4 h. The monomers, LA (11.0 g) and GA (3.4 g), were
added under dry argon atmosphere, and the reaction mixture
was heated under vacuum at 120 °C for 30 min. After all the
monomers were melted, stannous octoate (0.2 wt.%) was
added. Then, the reaction was allowed to proceed for 12 h at
160 °C under an atmosphere of argon. Upon completion of
the reaction, bath temperature was reduced to 150 °C, and
vacuum was applied to the reaction mixture for 30 min to
remove any unreacted monomers. The obtained crude
polymers were dissolved in ice cold water (4–8 °C). After
being completely dissolved, the polymer solution was
H NMR measurements of samples in deuteriochloroform
(CDCl3) were performed on a 500-MHz proton NMR
spectrometer (Bruker, DMX500 spectrometer) in order to
confirm the chemical structure and composition of the
copolymers [45]. MW and polydisperse indexes of copolymers denoted by weight-averaged MW Mw over Mn were
determined by gel permeation chromatography (GPC,
Agilent1100) with a differential refractometer as detector.
GPC measurements were performed at 35 °C in tetrahydrofuran as eluent at a flow rate of 1.0 mL/min. The MW
was calibrated with polystyrene as standard.
Determination of critical micellization concentration
The micellization was studied using the solubilization
method of a hydrophobic dye, 1,6-diphenyl-1,3,5-hexa-
Colloid Polym Sci (2010) 288:1151–1159
triene (DPH). The hydrophobic dye solution in methanol (10 μL at 0.4 mM) was injected into an aqueous
polymer solution (1 mL) in a polymer concentration
range of 0.001 to 0.2 wt.% and equilibrated overnight
at 4 °C. A UV–vis spectrophotometer was used to obtain
the UV–vis spectra in the range of 320–440 nm at 25 °C.
The critical micellization concentration (CMC) value
was determined by absorbance at 378 nm relative to
400 nm.
1153
Results and discussion
Block copolymer separation and characterization
Dynamic rheological analysis
The symmetric PLGA–PEG–PLGA copolymer was synthesized via ring-opening polymerization of LA and GA
initiated by two hydroxy end groups of PEG and catalyzed
by a Sn-complex. Conventional precipitate agents including
diethyl ether, hexane, and methanol were used to further
separate the copolymers after the preliminarily separated
products were dissolved in CH2Cl2, which is a very
common method used to separate the PEG/polyester
copolymers [7–11]. The obtained polymers were characterized by 1H NMR measurement with CDCl3 as a solvent. As
shown in Fig. 1, these spectra did not show any abnormal
characteristics compared to previous NMR measurements
of PLGA–PEG–PLGA block copolymers with different
chain lengths and PLGA composition, in which water [35,
46] or diethyl ether [7] was used as separation or precipitate
agents. We can find neither peaks of residual precipitate
agents nor significant difference between the spectra of the
samples separated by three different precipitate agents.
These features indicate that the amount of residual
precipitate agents is beyond the detection of NMR
measurement, namely, the amount is only minor.
The sol–gel transition of the copolymer aqueous solution
was also investigated in a dynamic strain-controlled
rheometer ARES (Rheometer Scientific) using a Couette
cell (Couette diameter, 34 mm; bob diameter, 32 mm;
bob height, 33.3 mm; bob gap, 2 mm). Cold polymer
solutions were transferred into the Couette cell and
carefully overlaid with a thin layer of low-viscosity
silicone oil to minimize solvent evaporation. During
temperature sweep experiments, appropriate strain amplitude was set according to preliminary tests to get both
the linearity of viscoelasticity and sufficient torque for
data collection. Temperature was played with an accuracy of ±0.05 °C by an environment controller (Neslab,
RTε130). The heating and cooling rates were set as
0.5 °C/min, while the angular frequency ω was set as
10 rad/s. Viscosity η was obtained from the real part of
complex viscosity associated with dissipative modulus G″
via η = G″/ω.
The test tube inverting method [37, 43] was further used
to determine sol or gel states. Each sample with a given
concentration was prepared by dissolving the polymer in
distilled water in a 2-mL vial and stored at 0 °C. After 24 h,
the vials with 0.5 mL of polymer solutions were immersed
in a water bath and allowed to reach equilibrium. The
sample was regarded as a “gel” in the case of no flow
within 30 s by inverting the vial with a temperature
increment of 1 °C per step.
Fig. 1 1H NMR spectra of copolymer-1 separated by the indicated
precipitate agents
Dynamic light scattering
Dynamic light scattering (DLS) was performed with a light
scattering spectrophotometer (Autosizer 4700, Malvern)
using a vertically polarized incident beam at 532 nm
supplied by an argon ion laser. The measurements were
made at the scattering angle of 90° and at the temperature
of 20 °C. Before each measurement, the sample was
filtrated through a 0.45-µm filter (Millipore) to remove
dust. The hydrodynamic radius of particles was calculated
following the Stokes–Einstein equation. The intensity–
intensity time correction function was analyzed by the
CONTIN method.
1154
Colloid Polym Sci (2010) 288:1151–1159
There was little difference between MW and its polydispersity for the copolymer separated by diethyl ether and
that by hexane, but the use of methanol led to a higher MW
and narrower polydispersity of the separated copolymer.
Solubility of corresponding polymeric blocks in good
and poor solvents
Fig. 2 GPC traces of copolymer-1 separated by the indicated
precipitate agents
According to a method described previously [45], the
number average MW of the PLGA–PEG–PLGA triblock
copolymer could be calculated by the peaks at 4.80, 3.60,
and 1.55 ppm in the 1H NMR spectra. GPC was further
performed to determine MW distribution. All of the GPC
traces of the triblock copolymers were unimodal with
polydisperse index (Mw/Mn) less than 1.23, indicating that
purity is sufficiently high to study their physical properties.
However, a difference of elution volume could still be
observed as shown in Fig. 2 for the obtained copolymer-1
using methanol versus other two precipitate agents.
Table 1 lists the calculated MWs, polydispersity, and
compositions of the copolymers measured by 1H NMR and
GPC in this study. The ratio of LA/GA is almost uniform
despite of different precipitate agents used in separation.
A question now arises: Why are MWs and polydispersities
of the copolymers altered using different precipitate agents?
One of the conventional separation approaches is to
dissolve a crude product or preliminarily separated polymer
in a good solvent and then precipitate the polymer in a poor
solvent (precipitate agent). While good solvents generally
are selected from methylene chloride, chloroform, dimethyl
sulfoxide, dimethyl formamide, etc., precipitate agents are
selected from diethyl ether, hexane, methanol, their mixtures, and so on. In our study, diethyl ether and hexane are
poor solvents for both PLGA and PEG blocks. In contrast,
methanol is a poor solvent for PLGA blocks but has a
certain solubility for PEG blocks especially when the
blocks are short.
According to our examinations, PEG (1,000) was
soluble in methanol over 1 g/mL at 25 °C, while the
solubility of PEG (20,000) in methanol was lower than
10 mg/mL. PLGA exhibits the MW dependence of
solubility as well. A series of PLGA with different MWs
was also synthesized, and their solubilities in methanol
were measured with the results listed in Table 2.
We found that the solubility of PLGA in methanol was
quite high if its MW is less than 2,000. In our case, the
precipitating capability of methanol is thus weaker than that
of diethyl ether or hexane. Any synthesized polymer has
Table 1 Molecular parameters of PLGA–PEG–PLGA triblock copolymers using different precipitate agents following dissolving polymers in
CH2Cl2
Sample and Mna
Precipitate agent
EG/LA/GA (mol/mol/mol)a
Mnb
Copolymer-1: 875-1000-875
Copolymer-1: 890-1000-890
Copolymer-1: 1360-1000-1360
Supernatant-1d 740-1000-740
Copolymer-2: 1410-1000-1410
Copolymer-2: 1400-1000-1400
Copolymer-2: 1650-1000-1650
Supernanant-2e 1050-1000-1050
Diethyl ether
Hexane
Methanol
Methanol
Diethyl ether
Hexane
Methanol
Methanol
2.91/2.41/1.00
2.88/2.43/1.00
1.84/2.35/1.00
3.49/2.45/1.00
1.35/1.60/1.00
1.36/1.60/1.00
1.13/1.55/1.00
1.84/1.64/1.00
3,820
3,820
5,560
3,160
5,430
5,500
6,590
3,910
(Mw/Mn)b
Yield (%)c
1.19
1.19
1.11
1.14
1.23
1.23
1.16
1.19
86.5
97.0
37.0
/
92.5
97.4
69.9
/
a
The number-averaged MW, Mn, of the central block PEG was provided by Aldrich. The molar ratio of ethylene glycol/lactide/glycolide (EG/LA/GA) and
Mn of each PLGA block were calculated by 1 H NMR
b
Measured via GPC
c
Yields in precipitation of preliminarily separated copolymers
d
Polymers collected from the supernatant after precipitation of copolymer-1 from its dichloromethane solution using methanol
e
Polymers collected from the supernatant after precipitation of copolymer-2 from its dichloromethane solution using methanol
Colloid Polym Sci (2010) 288:1151–1159
1155
Table 2 Molecular parameters and solubility in methanol of PLGA
Sample and Mna
PLGA-1:
PLGA-2:
PLGA-3:
PLGA-4:
590-116-590
1050-116-1050
1670-116-1670
3080-116-3080
LA/GA (mol/mol)a
2.84/1.00
2.83/1.00
2.66/1.00
2.74/1.00
Mnb
1,280
2,220
3,690
6,770
(Mw/Mn)b
Solubility in methanol (mg/mL)c
1.22
1.38
1.39
1.41
>200
<20
<10
<5
a
The “116” comes from the MW of 1,6-hexane diol, the initiator in ring-opening polymerization of PLGA. The molar ratio of lactide/glycolide (LA/GA)
and Mn of each PLGA block were calculated by 1 H NMR
b
Measured via GPC
c
Measured at 25 °C. Solubility in diethyl ether or hexane for all of PLGA examined were <5 mg/mL
inevitably a certain MW polydispersity. The block copolymers with long PLGA blocks can be precipitated due to
addition of methanol, but those copolymers with relatively
short PLGA blocks might still stay in the solution. As a
result, polymer with high MW and low polydispersity was
obtained by precipitation, as shown in Table 1. The residual
polymers collected from the supernatant after addition of
methanol exhibit a smaller MW, as was also reasonably
indicated in Table 1.
measured in dynamic rheological experiments. Figure 4
shows the change in storage modulus (G′) and viscosity (η)
of the PLGA–PEG–PLGA triblock copolymer aqueous
solution when the temperature was raised. The abrupt
increase of storage modulus and viscosity illustrates a sol–
gel transition. In Fig. 4a, the storage modulus increased
from 0.002 to 0.28 Pa for copolymer-1 separated by
CH2Cl2/diethyl ether or CH2Cl2/hexane with increasing
temperature, and our inverted vial experiments indicated
that these two samples just exhibited sol states throughout
Sol or gel behaviors of concentrated aqueous solutions
of block copolymers separated by three precipitate agents
After the obtained copolymers were mixed with water,
significantly different states were, however, observed at
room temperature (20 °C), as shown in Fig. 3. Although
copolymer-1 precipitated by diethyl ether or hexane was a
sol in water, the associated copolymer separated by
methanol exhibited a gel at 20 °C. Copolymer-2 separated
by diethyl ether or hexane also showed a gel at room
temperature; in contrast, the product separated by methanol
was insoluble in water. Obviously, our results reveal that
the average MW of PLGA block and its polydispersity have
a significant influence on the thermosensitivity of those
triblock copolymers in water.
It should be indicated that the associated images in Fig. 3
only show the states at room temperature. According to the
inverted vial tests, a sol state was observed in all of the
three thermogelling samples in Fig. 3 (copolymer-1/
methanol, copolymer-2/diethyl ether, and copolymer-2/
hexane) when lowering temperature till 7, 11, and 12 °C,
respectively. Another phenomenon is that a higher temperature in all of the three gel samples led to gel disruption and
eventual precipitation. In contrast, the two sol samples in
Fig. 3 (copolymer-1/diethyl ether, and copolymer-1/hexane)
did not exhibit a sol–gel transition upon heating. The last
sample (copolymer-2/methanol) only precipitated in the
examined temperature region (from 4 to 50°C).
The thermosensitivity of the PLGA–PEG–PLGA triblock copolymers in water was further quantitatively
Fig. 3 a Images of copolymer-1/water mixtures exhibiting sol, sol,
and gel states for copolymer-1 separated by resolving the preliminarily
separated product in CH2Cl2 and then using diethyl ether, hexane, or
methanol as a precipitate agent. Concentration, 10 wt.%; temperature,
20 °C. b Images of copolymer-2/water mixtures exhibiting gel, gel,
and precipitation states for copolymer-2 separated by the marked
precipitate agents. Concentration, 20 wt.%; temperature, 20 °C
1156
Colloid Polym Sci (2010) 288:1151–1159
Micellar behaviors of less-concentrated aqueous solutions
of block copolymers
According to our previous investigations of the physical
gelling mechanism of PLGA–PEG–PLGA in water, the
amphiphilic block copolymer are self-assembled into
micelles first, and the spontaneous gelling takes place via
packing of polymeric micelles [41]. A straightforward
observation of the percolated micelle network in the
physical gel is hard. In our recent work, the formation of
thermoreversible physical hydrogel by core crosslinked
micelles of another amphiphilic block copolymers strengthens the above mechanism [47]. The precipitate agent, which
can affect the macroscopic sol or gel states of our samples
in a concentrated aqueous system, might also influence the
Fig. 4 a Storage modulus G' and b viscosity of copolymer-1
separated by the indicated precipitate agents in aqueous solutions as
a function of temperature T in dynamic rheological measurements.
Concentration, 20, 20, and 10 wt.% of polymers separated using
diethyl ether, hexane, and methanol as precipitate agents, respectively
the examined temperature range. In contrast to it, the
storage modulus increased about four orders of magnitude
for copolymer-1 separated by CH2Cl2/methanol, and our
inverted vial experiments did observe a sol–gel transition.
For copolymer-2, the samples separated by diethyl ether
and hexane exhibited a significant sol–gel transition, as
observed in the inverted vial experiments. The quantitative
rheological measurements are shown in Fig. 5. There is no
rheological data for copolymer-2/methanol because this
sample cannot be dissolved in water. Another interesting
point is the difference of the sol–gel transition temperatures
for the samples copolymer-2/diethyl ether and copolymer-2/
hexane, while the MW difference as shown in Table 1 is
within the normal error range in GPC measurements. We
assume that the real MW, polydispersity index or PLGA
composition might still be of a bit difference, which is
beyond the resolution of GPC but sufficient for on or off of
a macroscopic thermogelling!
Fig. 5 a Storage modulus G' and b viscosity of copolymer-2
separated by the indicated precipitate agents in aqueous solutions as
a function of temperature T in dynamic rheological measurements.
Concentration, 20 wt.%; heating rates, 0.5 °C/min; oscillatory
frequency, 10 rad/s. The data of the copolymer-2 precipitated by
methanol are not available because the separated copolymer was not
dissolved in water as shown in Fig. 3b
Colloid Polym Sci (2010) 288:1151–1159
1157
sample separated by methanol is lower than both of the
samples separated by other two precipitate agents, which
could be understood that copolymer-1/methanol is of
higher MW and stronger hydrophobicity. The samples
separated by diethyl ether and hexane show similar MW
and CMC.
Micellar behaviors of the copolymers separated via three
different precipitate agents were further observed by DLS.
Figure 7 shows the intensity autocorrelation functions of
copolymer-1 in water at the sol state. The samples separated
by diethyl ether and hexane held low MW and were thus
relatively less hydrophobic. The associated micelles were
not further aggregated, and only one intensity peak
appeared at 20 °C. In contrast, the sample separated by
methanol possessed higher MW. Larger micelles were
observed under the same weight concentration of polymers
at the same observation temperature. Micellar aggregation
was also observed in Fig. 7 for copolymer-1/methanol,
which is a hint of further gelation in a concentrated aqueous
system if a percolated micelle network was formed.
Attribution of effects of precipitate agents to tuning
of balance of hydrophobicity and hydrophilicity
of resultant amphiphilic block copolymers
At length, we also found that upon a significantly different
PLGA or PEG block length (overly long or short), the
triblock copolymers did not exhibit the thermogelling
behaviors in water (data not shown). In our preceding
Fig. 6 a UV–vis spectra show the formation of micelles with
increasing copolymer concentration in water. The hydrophobic dye
(DPH) concentration was fixed at 4 μM, and polymer concentration
varied. For clarity, just five weight concentrations are shown in a. b
CMC determination of copolymer-1 separated by the indicated
precipitating agents by extrapolation of the difference of absorbance
at 378 and 400 nm. The measurements were done at 25 °C
micellar behaviors in a dilute or less-concentrated system.
Firstly, the CMC values were determined by the hydrophobic dye method in the presence of polymer at a low
concentration. As the block copolymers form core-coronalike micelles in water, the absorbance at 340, 356, and
378 nm increases due to the hydrophobic dye partitioning
into the hydrophobic cores of micelles (Fig. 6a). The
absorbance at 378 nm minus the absorbance 400 nm
(A378 −A400) versus logarithmic concentration was used to
determine CMC (Fig. 6b). Figure 6b shows that the CMC
of copolymer-1 separated by methanol at 25 °C is about
1.8×10−4 g/mL, and both of the samples separated by
diethyl ether and hexane are about 4.6 × 10−4 g/mL.
Similarly, the CMC values of copolymer-2 separated by
diethyl ether and hexane are almost the same (about 2.0×
10−4 g/mL). Comparing copolymer-1 separated via three
different precipitating agents, the CMC value of the
Fig. 7 Micellar sizes of copolymer-1 separated by the indicated
precipitate agents and then dissolved in water. The concentrations of
the aqueous solutions were 0.5 wt.%, and the DLS measurements
were made at 20 °C. Marked are hydrodynamic radii associated with
the peaks
1158
paper, it has been reported that the balance of hydrophobic
and hydrophilic blocks might be critical to exhibit a
thermoreversible sol–gel transition in water for some
PLGA–PEG–PLGA block copolymers [41]. The present
study further illustrates that based on the central PEG block
with MW of 1,000, the chain length of the PLGA block and
its polydispersity have very important influences on the
thermosensitivity of those triblock copolymers. Under a
certain hydrophilicity of the PEG block, the longer the
PLGA block chain length and the narrower its polydispersity is, the stronger the hydrophobicity of the PLGA block
is. It results in the lower CMC value, larger particle size,
and easier micellar aggregation. In a concentrated aqueous
system, a percolated micelle network is thus easily formed
at lower temperature, leading to the decrease of the sol–gel
transition temperature. An excessive hydrophilicity leads to
absence of physical gelation (only sols) due to difficulty to
form the percolated micelle network upon heating, while an
excessive hydrophobicity leads to macroscopic precipitation of the block copolymers in water.
As a result, this paper reports a significant effect of
precipitate agents used in polymer separation and essentially an effect of chain length, etc. All of these effects are
united into an effect of molecular composition or a delicate
balance of hydrophobicity and hydrophilicity. That is why
the obtained copolymers using different precipitate agents
exhibited much different aqueous behaviors.
Conclusions
PLGA–PEG–PLGA triblock copolymers were synthesized, and three precipitate agents were used to separate
those polymers. The polymer products separated by
methanol showed higher MW and narrower polydispersity
than those by ethyl ether and hexane. The difference
comes from the different precipitation capacities of
precipitate agents to PEG and PLGA blocks. The
influence was, however, so significant that the obtained
copolymers showed much different aqueous behaviors. In
some cases, the precipitate agents used in separation of
block copolymers even determined the occurrence of sol–
gel transition of the concentrated aqueous solutions of
collected polymers with increase of temperature, while
the polymers otherwise separated just exhibited sol or
precipitate states in water in the whole temperature range
examined. These results reveal that the hydrophobicity/
hydrophilicity balance determines the thermosensitivity of
some amphiphilic block copolymers in a selective
solvent. Our finding also illustrates that selecting an
appropriate precipitate agent is important during separation of a synthesized polymer, especially of this kind of
amphiphilic block copolymers.
Colloid Polym Sci (2010) 288:1151–1159
Acknowledgments The group was supported by the Chinese Ministry
of Science and Technology (973 Program No. 2009CB930000), NSF of
China (Grants No. 20774020 and No. 50903021), Science and
Technology Developing Foundation of Shanghai (Grants No.
074319117 and No. 09ZR1403700), the Specialized Research Fund
for the Doctoral Program of Higher Education of China (SRFDP;
No. 20090071120014), and Shanghai Education Committee (Project
No. B112).
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