Polycarbonate and poly(carbonate-ester)s synthesized from biocompatible building blocks of glycerol and lactic acid

Article abstract of DOI:10.1021/ma025872v

The synthesis and characterization of a polycarbonate of glycerol and poly(carbonate-ester)s of glycerol and L-lactic acid are reported. These new polymers possess a hydrolyzable backbone, tunable hydrophobic/hydrophilic properties, and functionalizable p

Full text of DOI:10.1021/ma025872v

Macromolecules 2003, 36, 3557-3562
3557
Polycarbonate and Poly(carbonate-ester)s Synthesized from
Biocompatible Building Blocks of Glycerol and Lactic Acid
Willia m C. Ra y, III a n d Ma r k W. Gr in sta ff*
Departments of Chemistry, Ophthalmology, and Biomedical Engineering, Duke University and
Duke University Medical Center, Durham, North Carolina 27708
Received November 25, 2002; Revised Manuscript Received March 4, 2003
ABSTRACT: The synthesis and characterization of a polycarbonate of glycerol and poly(carbonate-ester)s
of glycerol and L-lactic acid are reported. These new polymers possess a hydrolyzable backbone, tunable
hydrophobic/hydrophilic properties, and functionalizable pendant groups. The free hydroxyl groups on
the poly(glycerol-co-L-lactic acid) were derivatized with 4-isobutylmethylphenylacetic acid, a common
nonsteroidal antiinflammatory drug.
In tr od u ction
Resu lts a n d Discu ssion
Polymers find extensive use as medical materials,
ranging from simple nylon sutures to the first tissue-
engineered device, an artificial skin construct composed
of living cells.1-7 Since the 1960s, biodegradable syn-
thetic polymers, such as poly(L-lactide) (PLLA), have
been increasingly used in applications, such as drug
delivery, where long-term stability is not required.8-13
Copolymerization and blending of biodegradable poly-
mers can lead to a wide range of physical properties and
degradation rates, but functionalization of these poly-
mers is relatively limited. Few polymers with biocom-
patible and hydrolyzable backbones possess functional
or reactive pendant groups. This impedes the develop-
ment of advanced biomaterials with tailored chemical
functionality and optimized physical, mechanical, and
biological properties.
Several notable examples of functionalizable or bio-
logically inspired polymers are reported in the litera-
ture. These include linear polyesters such as poly(â-
malic acid),14,15 poly(L-serine ester),16,17 poly(glycolic
acid-co-malic acid),18 poly(5-hydroxy-ꢀ-caprolactone),19-26
poly(lactic acid-co-xylofuranose),27 and poly(lactic acid-
co-pentofuranose)28 as well as polyester-amides such
as poly(lactic acid-co-lysine),29,30 poly(lactic acid-co-as-
partic acid),31 and poly(depsipeptide)s.32,33 Two linear
polycarbonates are known, including poly(2-ethyl-2-
hydroxymethyltrimethylene carbonate)34 and poly(ty-
rosine carbonate).35,36 Recently, poly(ether-ester) and
polyester dendrimers composed of glycerol-lactic acid
and glycerol-succinic acid, respectively, are also de-
scribed.37-40 New biocompatible polymers are needed to
expand the current repertoire of customized biomate-
rials. Polymers are highly sought after that possess
functionalizable side chains (OH, NH2, CO2H, etc.),
alternative main-chain linkages, tunable degradation
rates, or other architectures such as comb, ladder, or
dendritic, while composed of building blocks that are
natural metabolites or known to be biocompatible. Here-
in, we report the synthesis and characterization of a
polycarbonate of glycerol and poly(carbonate-ester)s of
glycerol and L-lactic acid. These polymers possess a
hydrolyzable backbone, tunable hydrophobic/hydrophilic
properties, and functionalizable heteroatom pendant
groups.
As shown in Scheme 1, the polycarbonate of glycerol
was synthesized via ring-opening polymerization of a
cyclic glycerol carbonate using tin(II) 2-ethylhexanoate
(Sn(oct)2) followed by Pd catalyzed hydrogenation to
remove the benzyl (Bn) protecting group attached to
the secondary hydroxyl of glycerol.41,42 The monomer,
5-benzyloxy-1,3-dioxan-2-one, 3, was prepared in two
steps starting from cis-1,3-O-benzylideneglycerol (5-
hydroxy-2-phenyl-1,3-dioxane), 1.43 cis-1,3-O-Benzyli-
deneglycerol was treated with NaH and benzyl bro-
mide in THF to afford the doubly protected inter-
mediate, which was not isolated. The benzylidene group
was subsequently removed by acid hydroylsis (10%
aqueous HCl) to give 2-benzyloxy-1,3-propanediol, 2, in
98% yield. The diol was then converted to the cyclic
carbonate, 3, in 67% yield using ethyl chloroformate
and TEA in THF. Polymerization of neat 5-benzyloxy-
1,3-dioxan-2-one at 140 °C with Sn(oct)2 as catalyst
(monomer-to-catalyst ratio was 500:1) led to a modest
molecular weight polymer, 4 Bn . Under these polym-
erization conditions, longer reaction times neither in-
creased the molecular weight nor altered the polydis-
persity.
Poly(carbonate-ester)s of varying mole ratios of L-
lactic acid and glycerol were prepared in an analogous
manner (6 to 9), except using a higher reaction tem-
perature (180 °C). The benzyl-protected polymers (4 Bn ,
6 Bn to 9 Bn ) were subsequently deprotected using
Pd(OH)2/C and H2 to afford the polycarbonate of glyc-
erol, 4 OH, and poly(carbonate-ester)s of glycerol and
L-lactic acid (6 OH to 9 OH). The molecular weight
dependence as a function of mol % L-lactic acid monomer
for the poly(glycerol-co-L-lactic acid) is shown in Table
1. Under these polymerization conditions, L-lactide did
not undergo racemization; the specific optical rotation
for a sample of PLLA was -158°. This value agreed with
the reported value44 as well as a commercial sample
(Polysciences). This result is expected as the racemiza-
tion of lactide by Sn(oct)2-catalyzed polymerization does
not occur up to temperatures of 200 °C.45 Both NMR
and IR spectroscopy also provide additional evidence
for polymer formation. Polymerization of 5-benzyloxy-
1,3-dioxan-2-one, 3, leads to an IR carbonyl stretching
frequency shift from 1737 to 1746 cm-1 (∆ +9 cm-1
)
and a 13C NMR carbonyl resonance shift from 148.1 to
* Corresponding author: e-mail mark.grinstaff@duke.edu.
155.1 ppm (∆ +7.0 ppm; see Table 2). By comparison,
10.1021/ma025872v CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/24/2003

3558 Ray and Grinstaff
Macromolecules, Vol. 36, No. 10, 2003
Ta ble 1. Molecu la r Weigh t a n d Tg Da ta for th e
P olyca r bon a te a n d P oly(ca r bon a te-ester )sa
Sch em e 1. Syn th esis of a P olyca r bon a te of Glycer ol
(A) a n d P oly(ca r bon a te-ester )s of Glycer ol a n d
La ctic Acid (B) a n d a P oly(ca r bon a te-ester ) of
Glycer ol a n d La ctic Acid Der iva tized w ith a n NSAID
(C)a
mol %
lactic acid
b
polymer
Mw
PDI
% yield
70
Tg
4 Bn
4 OH
6 Bn
6 OH
7 Bn
7 OH
8 Bn
8 OH
9 Bn
9 OH
P LLA
10
0
0
12 000
8 600
12 800
10 900
11 500
9 700
18 200
17 400
30 800
16 700
44 900
8 400
1.76
1.43
1.65
1.62
1.46
1.67
1.48
1.57
1.21
1.58
1.79
1.42
6
25
25
50
50
70
70
90
90
100
50
70
78
70
84
18
30
20
34
24
53
33
60
38
85
90
a
All polymers were obtained by bulk polymerization for 2 h, at
b
140 °C (4) or 180 °C (6-9 and P LLA). Determined by size-
exclusion chromatography.
Ta ble 2. Sp ectr oscop ic Da ta for Mon om er s a n d
P olyca r bon a tes
carbonyl
stretch
(IR, neat)
carbonyl shift
(
13C NMR,
CDCl3)
monomer or polymer
5-benzyloxy-1,3-dioxan-2-one
poly(5-benzyloxy-1,3-dioxan-2-one)
trimethylene carbonate
1737
1746
1724
1738
148.1
155.1
148.2
154.9
poly(trimethylene carbonate)
neighbor.20,46,47 Thus, information on the sequence ar-
rangement (e.g., random, block, alternating) can be
obtained by analyzing the 13C NMR spectrum of the
copolymer. Analysis of the copolymer in terms of mono-
mer triads is a common method. We modeled48 the 13C
NMR spectrum for the eight triads possible for the two
repeating units, L-lactic acid, L, and glycerol, G (i.e.,
LLL, LLG, GLL, GLG, LGL, LGG, GGL, GGG). The 13C
NMR resonances for the LLL and GGG triads were
assigned from the respective homopolymers (i.e., PLLA
and 4 Bn ); the remainder were predicted using NMR
simulation software (see Figure 1).48 As expected, a
single resonance is found for the carbonyls of the
homopolymers. However as seen in Figure 1, four
resonances are found in the carbonyl region for the 30%
carbonate copolymer (8Bn ). The resonance at 169.7 ppm
is assigned to the LLL triad, which is the most prevalent
sequence in the copolymer. In addition, there is a
resonance just downfield at 169.9 ppm. This signal is
attributed to the central carbonyl in the LLG triad. For
the carbonate carbonyl, the resonance appears at 154.4
ppm, slightly upfield from its position in the homopoly-
mer (154.8 ppm). This resonance is assigned to the
central carbonyl in the LGL triad. Similar data are
observed with the 10% carbonate copolymer (9Bn ),
except that the signal at 154.8 ppm for the GGG triad
is absent. These data indicate that the copolymers are
statistical copolymers.
Polymers 4 and 6 through 9 displayed a range of
physical properties consistent with their chemical com-
position. The benzyl-protected polycarbonate and poly-
(carbonate-ester)s were soluble in halogenated sol-
vents, aromatic solvents, THF, and ethyl acetate. The
free-hydroxy polycarbonate and poly(carbonate-ester)s
were soluble in hydrophilic solvents such as DMF and
MeOH. Polymer 4 OH was soluble in water, and
copolymers 6 OH to 9 OH become more hydrophobic
with increasing mol % L-lactic acid in the polymer.
Thermal analysis of the copolymers by differential
scanning calorimetry revealed two trends. First, the
a
Reagents and conditions: a. i. NaH, THF, ii. BnBr, iii. 10%
aq HCl; b. i. EtOCOCl, THF, ii. Et3N; c. Sn(Oct)2; d. H2,
Pd(OH)2/C; e. 4-isobutylmethylphenylacetyl chloride, Et3N,
CH2Cl2.
polymerization of trimethylene carbonate leads to an
IR carbonyl frequency shift from 1724 to 1738 cm-1
(∆ +14 cm-1) and a 13C NMR carbonyl resonance shift
from 148.2 to 154.9 ppm (∆ +6.7 ppm). Removal of
the Bn group of the secondary hydroxyl of 4 Bn and 6
Bn to 9 Bn afforded a new IR OH stretch at 3400
cm-1. The similarities in the IR and NMR shifts be-
tween poly(trimethylene carbonate) and poly(glycerol
carbonate) and their corresponding monomers sup-
port the formation of the polycarbonate. NMR analy-
sis of the copolymers shows that the ratio of L-lactic
acid to glycerol in the copolymer correlated reasonably
well with the starting monomer ratio. For example, a
mol % starting ratio of 1:1 for monomers 3 and 5 affords
a copolymer composed of 60% lactic acid and 40%
glycerol.
In the poly(carbonate-ester)s the 13C NMR reso-
nances of the monomers vary with the copolymer se-
quence, each monomer unit being sensitive to its nearest

Macromolecules, Vol. 36, No. 10, 2003
Polycarbonate and Poly(carbonate-ester)s 3559
F igu r e 1. 13C NMR spectra of P LLA, 8Bn , and 4Bn and the chemical structures of the eight triads possible with the respective
carbonyls noted.
copolymer glass transition temperature (Tg) increased
with decreasing glycerol content, from 6 °C for 4Bn to
60 °C for PLLA. These data are given in Table 1. Second,
introduction of glycerol-carbonate linkages to the poly-
(L-lactide) chain led to a significant reduction of the
crystallinity of the polymer. For a sample of PLLA a
crystallization was observed at approximately 109 °C,
followed by a melt (Tm) at 171 °C (∆Hf ) 32 J /g). A
sample of 9Bn crystallized at 130 °C, followed by a Tm
of 151 °C (∆Hf ) 1.5 J /g). Analysis of the copolymers
with higher glycerol content indicated no crystallinity.
The degradation of the poly(carbonate-ester)s was
next investigated at neutral pH (pH ) 7.4), at acidic
pH (pH ) 4.4), and in the presence of an esterase.
Samples of 1 cm2 films of 8 OH, 9 OH, and PLLA were
submerged in a 0.1 molar buffered phosphate solution
of the appropriate condition at 37 °C. Samples were then
measured at 1, 2, 4, 7, 10, and 14 day intervals, and
the molecular weight of the polymer was determined
by size-exclusion chromatography. Under neutral and
mild acidic conditions the poly(carbonate-ester)s, 8 OH
F igu r e 2. Degradation of copolymer 9 OH at pH ) 7.4 (solid
and 9 OH, degraded while PLLA remained essentially
unchanged. After 14 days, the molecular weight had
decreased by approximately 35% for both copolymers.
Degradation was slightly greater at pH ) 4.4. Data for
copolymer 9 OH, for example, are shown in Figure 2.
The presence of porcine liver esterase also does not effect
significantly the degradation of the polymers. The
physical appearance of the polymer samples did not
triangle), at pH ) 4.4 (open squares), and in the presence of
an esterase (solid circles).
appreciably change. The poly(carbonate-ester)s were
more susceptible to hydrolytic degradation than PLLA
consistent with the decreased crystallinity present in
the copolymers. A similar conclusion was reported for
poly(lactic acid-co-lysine).30

3560 Ray and Grinstaff
Macromolecules, Vol. 36, No. 10, 2003
10 °C/min to 125 °C, cool 10 °C/min to -25 °C, ramp 10 °C/
min to 125 °C); thermal transitions were measured on the
second heating cycle. The optical rotation of the polymers was
measured in dichloromethane at a concentration of 0.025 g/mL
at 26 °C using a Rudolph Autopol IV automatic polarimeter
at a wavelength of 589 nm. THF ) tetrahydrofuran, EtOAc )
ethyl acetate, Pd/C ) 10% palladium on activated carbon,
PLLA ) poly(L-lactide), PCG ) polycarbonate of glycerol.
Syn th esis of 2-Ben zyloxy-1,3-p r op a n ed iol. Sodium hy-
dride (5.0 g 60% in mineral oil, 0.125 mol) was suspended in
freshly distilled THF (400 mL), and the mixture was cooled
in an ice/H2O bath. 5-Hydroxy-2-phenyl-1,3-dioxane (18.2 g,
0.100 mol) was added in portions, and the mixture was stirred
for 15 min. Benzyl bromide (14.4 mL, 0.120 mol) was added
via a syringe, and the reaction was stirred at 0 °C to room
temperature (RT) overnight. Approximately half of the THF
was evaporated under reduced pressure, and 100 mL of H2O
and 300 mL of 10% aqueous HCl were added. The mixture
was refluxed for 2 h, cooled to room temperature, and poured
into 50 mL of saturated aqueous Na2CO3. The solution was
extracted with ethyl acetate (3 × 50 mL). The extracts were
dried over Na2SO4 and evaporated to yield 18.0 g (98% yield)
of a viscous residue. The product was used without further
purification. A small portion, purified by vacuum distillation
(149 °C/0.2 mmHg), solidified upon freezing; mp ) 35-37 °C
(lit. 38.5-40 °C). 1H NMR (CDCl3): 2.02 (s, 2H, CH2OH), 3.56
(m, 1H, OCH), 3.67-3.78 (m, 4H, CH2OH), 4.67 (s, 2H,
PhCH2), 7.23-7.34 (m, 5H, aromatic). IR (neat) 2881, 2927,
The free hydroxyl group on the glycerol-lactic acid
copolymer is amenable to functionalization, and this
provides opportunities for covalent attachment of bio-
logical epitopes for cell recognition, photo-cross-linkable
moieties for 3D-gel formation, or pharmaceutical agents
for drug delivery. Nonsteroidal antiinflammatory drugs
(NSAIDs) represent a large class of pharmaceuticals
widely used as antiinflammatories, analgesics, or anti-
pyretics.49 The therapeutic actions of NSAIDS arise
from altering prostaglandin production by inhibiting the
cyclo-oxygenase (COX) enzyme.50 One common NSAID
used to treat rheumatoid arthritis and osteoarthritis is
4-isobutylmethylphenylacetic acid. Derivatization of the
poly(glycerol-co-L-lactic acid), 7 OH, with an excess of
4-isobutylmethylphenylacetyl chloride afforded the
NSAID functionalized copolymer 10. Size exclusion
chromatography revealed the weight-average molecular
weight to be 8400. The unique aromatic protons of
4-isobutylmethylphenylacetate at 7 ppm were observed
in the NMR spectrum of 10, and integration of the
proton resonances of the copolymer indicated that ∼90%
of the hydroxyls were modified with this NSAID.
Con clu sion
In summary, aliphatic polycarbonates with glycerol
repeating units are synthesized by ring-opening polym-
erization of 5-benzyloxy-1,3-dioxan-2-one followed by
catalytic hydrogenolysis. Copolymers with L-lactide can
be prepared suggesting that other cyclic carbonates and
lactones are likely monomers for tailored copolymers.
These polymers offer several advantages including
functionalizable side chains for modification, known
biocompatible units of glycerol and lactic acid, and a
tunable hydrophilic structure. Optimization of the
chemical, physical, and mechanical properties of such
polymers through judicious choice of the monomer(s) is
likely to facilitate the synthesis of new polymers de-
signed for specific drug delivery and tissue engineering
applications.
3375 cm-1
.
Syn t h esis of 5-Ben zyloxy-1,3-d ioxa n -2-on e. 5-Benzyl-
oxy-1,3-dioxan-2-one was previously reported in 1983 by
Schaeffer as an intermediate in the synthesis of several
antiviral compounds.43 5-Benzyloxy-1,3-propanediol (10.5 g)
and ethyl chloroformate (20.3 mL, 0.21 mol) were dissolved
in freshly distilled THF (250 mL). The solution was stirred at
0 °C under N2 for 15 min. Triethylamine (31.0 mL, 0.22 mol)
was added via a dropping funnel over 30 min. The reaction
was then stirred at 0 °C to RT for 3 h. The solid precipitate
was removed by filtration, and the solvent was evaporated to
yield 12 g (67% yield). The residue was recrystallized from
THF/diethyl ether to yield 4.0 g white crystals; mp ) 120-
121 °C. 1H NMR (CDCl3): 3.89 (p, J ) 2.7 Hz, 1H, OCH), 4.41-
4.51 (m, 4H, OCH2CH), 4.65 (s, 2H, PhCH2), 7.33-7.40 (m,
5H, aromatic). 13C NMR: 66.35, 69.93, 71.06, 128.08, 128.63,
129.03, 136.91, 148.12. IR (neat): 1737 (CdO)cm-1. HR FAB
MS: M/Z+: 209.0811 (209.0815 calculated). Elemental analy-
sis: C, 63.64; H, 5.97 (calculated: C, 63.45; H, 5.81).
Exp er im en ta l Section
Gen er a l P r oced u r es. All solvents were dried and freshly
distilled prior to use. THF and toluene were distilled under
N2 from sodium; methanol and CH2Cl2 were distilled under
N2 from calcium hydride. All other reagents were used as
received, without further purification. Glycerol, benzaldehyde,
sodium hydride (60% in mineral oil), benzyl bromide, ethyl
chloroformate, triethylamine, and palladium on carbon were
purchased from Acros. Stannous 2-ethylhexanoate (stannous
octoate), LL-lactide, and R-methyl-4-(isobutyl)phenylacetic acid
were purchased from Aldrich. cis-1,3-O-Benzylideneglycerol
was either purchased from Aldrich or prepared according to
the literature,51 and R-methyl-4-(isobutyl)phenylacetyl chloride
was also prepared according to the literature.52 All reactions
were performed under a nitrogen atmosphere unless otherwise
noted. NMR spectra were recorded on a Varian INOVA
spectrometer (for 1H and 13C at 400 and 100.6 MHz, respec-
tively). FT-IR spectra were recorded on a Nicolet Smart
MIRacle Avatar 360 using a zinc selenide crystal. Chemical
ionization mass spectra were obtained on a Hewlett-Packard
HP 5988A spectrometer using NH3. Fast atom bombardment
mass spectra (FABMS) were obtained on a J EOL J MS-SX102A
spectrometer using a 3-nitrobenzyl alcohol matrix. Elemental
analysis was obtained from Atlantic Microlab, Inc. Size exclu-
sion chromatography was performed using THF as the eluent
on a Polymer Laboratories PLgel 3 µm MIXED-E column (3
µm bead size) and a Rainin HPLC system (temperature ) 25
°C; flow rate ) 1.0 mL/min). Polystyrene standards (Poly-
sciences, Inc.) were used for calibration. A TA Instruments
DSC 2920 modulated DSC was used to collect Tg data (ramp
P olym er ization of 5-Ben zyloxy-1,3-dioxan -2-on e. 5-Ben-
zyloxy-1,3-dioxan-2-one (520.5 mg, 5.00 mmol) was placed in
a 10 mL Schlenk flask. The reaction vessel was evacuated and
flushed with N2 three times. Next, the reaction vessel was
partially immersed in a thermostated oil bath, preheated to
140 °C. After 5 min, the catalyst (0.10 M solution of Sn(Oct)2
in toluene, 500/1 monomer/catalyst ratio) was added via a
syringe. The reaction was cooled to room temperature after 2
h. The polymer was dissolved in dichloromethane (10 mL) and
precipitated into cold methanol (25 mL). The polymer was then
isolated by filtration (362 mg, 70% yield). 1H NMR (CDCl3):
3.84 (broad p, J ) 5.0 Hz, 1H, OCH), 4.19-4.31 (m, 4H, OCH2-
CH), 4.64 (s, 2H, PhCH2), 7.27-7.35 (m, 5H, aromatic). 13C
NMR: 66.82, 72.63, 74.31, 128.18, 128.37, 128.80, 137.84,
155.10. IR (neat): 1746 (CdO) cm-1
.
Copolym er ization of 5-Ben zyloxy-1,3-dioxan -2-on e an d
L-La ctid e. L-Lactide and 5-benzyloxy-1,3-dioxan-2-one (com-
bined total of 10 mmol) were placed in a 10 mL Schlenck flask.
The reaction vessel was sealed, evacuated, and purged with
N2 three times. Next, the reaction vessel was partially im-
mersed in a thermostated oil bath, preheated to 180 °C. After
5 min, a 50 µL solution of 0.50 M solution Sn(Oct)2 in toluene
(monomer/catalyst ratio ) 200:1) was added via a syringe. The
reaction was stirred at 180 °C for 2 h and then cooled to room
temperature. The cooled copolymer was dissolved in minimal
CH2Cl2 and precipitated into cold MeOH. The copolymer was
then isolated by filtration and dried under vacuum. The yields
for 6 Bn -9 Bn ranged from 60 to 75%. The NMR and IR

Macromolecules, Vol. 36, No. 10, 2003
Polycarbonate and Poly(carbonate-ester)s 3561
(3) Christenson, L.; Mikos, A. G.; Gibbons, D. F.; Picciolo, G. L.
spectra were similar for all the copolymers. For example, the
characterization data for compound 6 Bn include the follow-
ing: 1H NMR (CDCl3): 1.46-1.56 (broad m, PLLA CH3), 3.81
(broad, PCG CH), 4.20-4.23 (broad, PCG CH2), 4.61 (broad,
PCG benzyl CH2), 4.97-5.15 (broad, PLLA CH), 7.23-7.29
(broad, PCG aromatic). IR (neat): 1748 cm-1 (lactide and
carbonate CdO).
Tissue Eng. 1997, 3, 71-76.
(4) Langer, R.; Vacanti, J . P. Science 1993, 260, 920-926.
(5) Peppas, N. A.; Langer, R. Science 1994, 263, 1715-1720.
(6) Ratner, B. D.; Hoffman, A. S.; Schoen, F. J .; Lemons, J . E.
Biomaterials Science: An Introduction to Material in Medi-
cine; Academic Press: San Diego, 2000.
Hyd r ogen olysis of Ben zyla ted P olym er s. The homopoly-
mer (poly(5-benzyloxy-1,3-dioxan-2-one) (300 mg) or copolymer
(poly(5-benzyloxy-1,3-dioxan-2-one-co-L-lactide) (300 mg) was
dissolved in 25 mL of dry THF. 10% Pd/C (50 mg) and 20%
Pd(OH)2/C (50 mg) was then added to this solution. The
reaction mixture, in a Parr bottle, was evacuated and purged
with H2 three times. The flask was then pressurized to 60
psi with hydrogen and shaken for 24 h. The reaction mixture
was filtered through Celite and the filter cake washed with
50 mL of THF. The solvents were then evaporated to yield
the final polymer (quantitative yield). The NMR and IR spectra
were similar for all the copolymers. For example, the charac-
terization data for compound 6 OH include the following: 1H
NMR (CDCl3): 1.55-1.58 (broad m, PLLA CH3), 4.13-4.22
(broad, PCG CH, CH2), 5.12-5.15 (broad, PLLA CH). IR
(neat): 1747 cm-1 (lactide and carbonate CdO), 3503 cm-1
(OH).
(7) Griffith, L. G.; Naughton, G. Science 2002, 295, 1009-1014.
(8) Frazza, E. J .; Schmitt, E. E. J . Biomed. Mater. Res. Symp.
1971, 1, 43-58.
(9) Shalaby, S. W.; J ohnson, R. A. Biomed. Polym. 1994, 2-34.
(10) Uhrich, K. E.; Cannizzaro, S. M.; Langer, R.; Shakesheff, K.
M. Chem. Rev. 1999, 99, 3181-3198.
(11) Vert, M.; Li, S. M. J . Mater. Sci.: Mater. Med. 1992, 3, 432-
446.
(12) Vert, M.; Feijen, J .; Albertsson, A. C.; Scott, G.; Chiellini, E.
In Biodegradable Polymers and Plastics; Royal Society:
London, 1992.
(13) Hench, L. L.; Polak, J . M. Science 2002, 295, 1014-1017.
(14) Gue´rin, P.; Vert, M.; Braud, C.; Lenz, R. W. Polym. Bull.
(Berlin) 1985, 14, 187-192.
(15) Cammas-Marion, S.; Gue´rin, P. Macrmol. Symp. 2000, 153,
167-186.
(16) Zhou, Q. J .; Kohn, K. Macromolecules 1990, 23, 3399-3406.
Ester ification of Fr ee-Hydr oxy Gr ou ps with of 4-Isobu -
tylm eth ylp h en yla cetic Acid (Ibu p r ofen ). The free-OH
copolymer (7 OH , 20 mg) was dissolved in 5 mL of dry
CH2Cl2. Triethylamine (46 mg in 1 mL of CH2Cl2, 3 equiv) was
added, and the solution was cooled in an ice/H2O bath. Next,
4-isobutylmethylphenylacetyl chloride (34 mg in 1 mL of
CH2Cl2, 1 equiv) was added dropwise. The reaction was stirred
at 0 °C for 5 min and quenched by the addition of H2O. The
organic layer was washed twice with 1% (w/v) Na2CO3(aq),
dried by Na2SO4, and evaporated to yield the functionalized
polymer. 1H NMR: 0.86 (d, J ) 6.5 Hz, 6H, ibuprofen isobutyl
CH3), 1.45 (d, J ) 5.6 Hz, 3H, ibuprofen CH3), 1.55-1.57
(broad, 6H, PLLA CH3), 1.81 (m, 1H, ibuprofen isobutyl CH),
2.41 (d, J ) 7.0 Hz, 2H, ibuprofen CH2), 3.69 (broad, 1H,
ibuprofen CH), 4.10-4.40 (broad, 5H, PCG CH, CH2), 5.10-
5.25 (broad, 1H, PLLA CH), 7.05 (m, 2H, ibuprofen aromatic),
7.15 (m, 2H, ibuprofen aromatic).
(17) Gelbin, M. E.; Kohn, J . J . Am. Chem. Soc. 1992, 114, 3962-
3965.
(18) Kimura, Y.; Shirotani, K.; Yamane, H.; Kitao, T. Macromol-
ecules 1998, 21, 3338-3340.
(19) Tian, D.; Dubois, P.; Grandfils, C.; J e´roˆme, R. Macromolecules
1997, 30, 406-409.
(20) Tian, D.; Dubois, P.; Grandfils, C.; J e´roˆme, R. Macromolecules
1997, 30, 2575-2581.
(21) Mecerreyes, D.; Atthoff, B.; Boduch, K. A.; Trollsas, M.;
Hedrick, J . L. Macromolecules 1999, 32, 5175-5182.
(22) Detrembleur, C.; Mazza, M.; Lou, X.; Halleux, O.; Lecomte,
P.; Mecerreyes, D.; Hendrick, J . L.; J e´roˆme, R. Macromol-
ecules 2000, 33, 7751-7760.
(23) Detrembleur, C.; Mazza, M.; Halleux, O.; Lecomte, P.; Mecer-
reyes, D.; Hendrick, J . L.; J e´roˆme, R. Macromolecules 2000,
33, 14-18.
(24) Stassin, F.; Halleux, O.; Dubois, P.; Detrembleur, C.; Lecomte,
Degr a d a tion Stu d ies. Polymers were either pressed into
1-2 mm thick pellets (PLLA) or cast into 1-2 mm thick films
(10% carbonate and 30% carbonate) which were cut into 1
cm2 squares. The polymer samples were then submerged in
0.1 molar buffered phosphate or phosphate/citrate solu-
tions; neutral solution (pH ) 7.4), enzyme solution (pH ) 7.4,
plus 2 IU/mL porcine liver esterase), acidic solution (pH ) 4.4).
The immersed samples were incubated at 37 °C, and three
samples of each polymer/solution combination were isolated
at intervals of 1, 2, 4, 7, 10, and 14 days. The molecular weight
of the polymer samples was determined by size-exclusion
chromatography.
P.; J e´roˆme, R. Macromol. Symp. 2000, 153, 27-39.
(25) Trollsas, M.; Lee, V. Y.; Mecerreyes, D.; Lo¨wenhielm, P.;
Mo¨ller, M.; Miller, R. D.; Hendrick, J . L. Macromolecules
2000, 33, 4619-4627.
(26) Latere, J . P.; Lecomte, P.; Dubois, P.; J e´roˆme, R. Macromol-
ecules 2002, 35, 7857-7858.
(27) Chen, X.; Gross, R. H. Macromolecules 1999, 32, 308-314.
(28) Kumar, R.; Gao, W.; Gross, R. H. Macromolecules 2002, 35,
6835-6844.
(29) Barrera, D. A.; Zylstra, E.; Lansbury, P. T.; Langer, R. J .
Am. Chem. Soc. 1993, 115, 11010-11011.
(30) Barrera, D. A.; Zylstra, E.; Lansbury, P. T.; Langer, R.
Macromolecules 1995, 28, 425-432.
(31) Elisseeff, J .; Anseth, K.; Langer, R.; Hrkach, J . S. Macro-
molecules 1997, 30, 2182-2184.
Ack n ow led gm en t. This research was supported in
part by the Pew Scholars Program in the Biomedical
Sciences and the NIH (R01-EY13881). W.C.R. gratefully
acknowledges the NIH Pharmacology Training Grant
Program at Duke University. M.W.G. also thanks the
Dreyfus Foundation for a Camille Dreyfus Teacher-
Scholar, the 3M Corporation for a Non-Tenured Faculty
Award, the J ohnson and J ohnson Foundation, and the
Alfred P. Sloan Foundation for a Research Fellowship.
(32) Helder, J .; Kohn, F. E.; Sato, S.; van den Berg, J . W.; Feijen,
J . Makromol. Chem., Rapid Commun. 1985, 6, 9-14.
(33) Helder, J .; Lee, S. J .; Kim, S. W.; Feijen, J . Makromol. Chem.,
Rapid Commun. 1986, 7, 193-198.
(34) Kuhling, S.; Keul, H.; Ho¨cker, H. Makromol. Chem. 1991,
192, 1193-1205.
(35) Pulapura, S.; Kohn, J . Biopolymers 1992, 32, 411-417.
(36) Ertel, S. I.; Kohn, J . J . Biomed. Mater. Res. 1994, 28, 919-
930.
Su p p or tin g In for m a tion Ava ila ble: SEC graphs. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(37) Carnahan, M. A.; Grinstaff, M. W. J . Am. Chem. Soc. 2001,
123, 2905-2906.
(38) Carnahan, M. A.; Grinstaff, M. W. Macromolecules 2001, 34,
7648-7655.
Refer en ces a n d Notes
(39) Carnahan, M. A.; Middleton, C.; Kim, J .; Kim, T.; Grinstaff,
M. W. J . Am. Chem. Soc. 2002, 124, 5291-5293.
(40) Grinstaff, M. W. Chem.sEur. J . 2002, 8, 2838-2846.
(1) Lanza, R. P.; Langer, R.; Chick, W. L. Principles of Tissue
Engineering; R.G. Landes/Academic Press: San Diego, CA,
1997.
(41) Ray, W. C.; Grinstaff, M. W. Polym. Prepr. 2001, 42, 123-
(2) Sci. Am. 1999 (April).
124.

3562 Ray and Grinstaff
Macromolecules, Vol. 36, No. 10, 2003
(42) Wang, X. L.; Zhuo, R.; Liu, J .; He, F.; Liu, G. J . Polym. Sci.,
Part A 2001, 40, 70-75.
(43) Schaeffer, H. J . European Patent 82-107247, 1983.
(44) Tsuji, H.; Ikada, Y. Macromolecules 1992, 25, 5719-5723.
(45) Kricheldorf, H. R. Macromol. Symp. 2000, 153, 55-65.
(46) Kricheldorf, H. R.; J onte´, J . M.; Berl, M. Makromol. Chem.
Suppl. 1985, 12, 25.
(49) Lewis, A. J .; Furst, D. E. Nonsteroidal Anti-infammatory
Drugs: Mechanisms and Clinical Uses; Dekker: New York,
1994.
(50) Smith, W. L.; DeWitt, D. L.; Garavito, R. M. Annu. Rev.
Biochem. 2000, 69, 145-182.
(51) Carlsen, P. H. J .; Sorbye, K.; Ulven, T.; Aasbo, K. Acta Chim.
Scand. 1996, 50, 185-187.
(52) Saavfedra, J . E.; Booth, M. N.; Hrabie, J . A.; Davies, K. M.;
Keefer, L. K. J . Org. Chem. 1999, 64, 5124.
(47) Schmidt, P.; Keul, H.; Ho¨cker, H. Macromolecules 1996, 29,
3674-3680.
(48) CDSLABS INC 13 NMR software.
MA025872V