ECOLE DE PHARMACIE GENEVE-LAUSANNE: A NOVEL CENTER OF EXCELLENCE IN GENEVA
349
CHIMIA 2005, 59, No. 6
lished PLA/PLGA systems. By this differ- ethyl acetate/hexane mixture 1:2. After fil-
ent functional PLAs with tailored material tration over silica gel the solvents were dis-
properties for biomedical applications can tilled off, and the remaining crude product
Viscosity Determination
Viscosities were determined using a
Bohlin controlled stress rheometer with a
parallel plate PU 20 device (Bohlin Rheol-
ogy GmbH, Mühlacker, Germany). A stress
viscosity test (rotation) was applied to the
samples which were placed on the station-
ary lower plate. The temperature was fixed
at 25 °C or 37 °C during the test with a Boh-
lin Extended Temperature Option (ETO).
Shear rates ranging from 0.1 to 400 s–1 were
used for determination. For all samples an
integration time of 20 s and a delay time of
20 s were used.
be easily obtained.
was recrystallized from hexane at –20 °C.
We present here a detailed study on the Yield: 45%; 1H NMR (500 MHz, CDCl3): δ
synthesis and controlled ROP of these nov- 5.00 (q, 1H), 4.89 (dd, 1H), 1.9–2.15 (br m,
el hexyl-substituted polylactides, as well as 2H), 1.70 (d), 1.66 (d), (3H, of 2 diastereo-
their physico-chemical properties in terms mers), 1.45–1.65 (br m, 2H), 1.25–1.40 (br
of Tg and rheological behavior and degra- m, 6H), 0.90 (t, 3H). 13C NMR (500 MHz,
dation kinetics and mechanism.
CDCl3): δ 167.53, 166.90. 166.26, 165.87,
75.80, 72.49, 72.25, 31.92, 31.45, 31.39,
30.00, 28.73, 28.50, 24.60, 24.29, 22.48,
22.44, 17.54, 15.83, 14.00.
Materials and Methods
Materials
Polymer Synthesis and
Heptaldehyde, 2-bromopropionyl bro- Characterization
Degradation Studies
mide,
and
4-dimethylaminopyridine
Polymerizations were typically run with
2.0 g of monomer 4 in bulk (hexyl-substitut-
ed lactide) or in toluene (D,L-lactide) in the
presence of Sn(Oct)2 as catalyst and benzyl
alcohol as initiator in equimolar amounts.A
reaction flask containing a stirbar was fitted
with a septum, flamed under vacuum, and
placed into a glove-box where the monomer
4 was filled in. In a typical procedure (for a
targeted degree of polymerization [DP] of
30), 2.0 g monohexyl-substituted lactide
(9.34 mmol) were heated for melting and
360 μl Sn(Oct)2 stock solution (0.35 g/ml in
dry THF) and 160 μl benzyl alcohol (from
a 5-fold diluted stock solution in dry THF
(0.310 mmol)) were added under argon at-
mosphere, and the mixture was heated to
100 °C. The procedure was typically the
same for D,L-lactide polymerization except
that dry toluene was added to the monomer
for solubilization before addition of the
catalyst and initiator.
40 mg of polymer were placed into
flasks and gently heated to be above the Tg
of the polymers. 5 ml of 0.1 M phosphate
buffer pH 7.4 were then added and the flasks
slowly agitated at the adequate temperature.
At predetermined times polymers were col-
lected, rinsed with milli-Q water and dried
to constant weight prior to determination of
mass loss and average molecular weight.
Mass loss (ML%) was evaluated by
gravimetric analysis and calculated from:
(DMAP) were purchased from Fluka (Bu-
chs, Switzerland). D,L-lactide from Purac
Biochem (The Netherlands) was delivered
under vacuum and directly transferred into
a glove-box for storage. Tin(II) 2-ethyl-
hexanoate (Sn(Oct)2) was purchased from
Aldrich (Buchs, Switzerland) and used as
received. Benzyl alcohol (Fluka) was suc-
cessively dried over anhydrous magnesium
sulfate and sodium and distilled prior to
use. Solvents were dried by standard meth-
ods and distilled prior to use.
Monomer Synthesis
2-Hydroxyoctanoic acid (2)
To 78 g NaHSO3 (0.75 mol) in water (1
l) heptaldehyde (57 g, 0.5 mol) was added
under vigorous stirring for 30 min; then a
solution of NaCN (32 g, 0.65 mol) in water
(250 ml) was added and the mixture was
shaken for 15 min. The upper layer upon
separation of phases was poured directly in-
to a solution of 40 v% sulfuric acid (165 ml)
and heated at 125 °C for 3 h, then poured
into 6 M NaOH (500 ml) and stirred for 12
h. The alkaline solution was washed with
Et2O (2 × 150 ml) then acidified with 2 M
HCl and extracted with Et2O (3 × 150 ml)
which was washed with brine (100 ml),
dried, and evaporated. Recrystallization
from toluene gave 47 g (59%) of pure prod-
where W0 and Wt are the initial weight
and residual weight of the dry polymer at
time t.
Molecular weights were determined by
GPC by dissolving the polymer in THF as
described above.
At the desired reaction time the reac-
tions were stopped by adding 10 ml of THF,
followed by precipitation in cold methanol
and drying at 40 °C under vacuum. Poly-
merization conversions and DP were deter-
mined by 1H NMR analysis, and molecular
weights and polydispersities by gel perme-
ation chromatography.
Results and Discussion
Monomer Synthesis and Controlled
ROP
In our previous work we reported the
synthesis and ring-opening polymerization
of novel alkyl-substituted lactide mono-
mers for the design of new tailored poly-
lactide materials [12]. Here we focus on
the poly(monohexyl-substituted lactide)
(PmHLA, 5) which was obtained by the
synthesis pathway presented in Scheme 1.
The synthesis of the new monohexyl-sub-
stituted lactide (mHLA, 4) is based on a
‘two step one pot’reaction of 2-hydroxyoc-
tanoic acid (2), easily synthesized in large
scale from heptanal (1), with 2-bromopro-
pionyl bromide leading to an intermediate
ester 3, which undergoes ring closure after
changing to basic reaction conditions with
triethylamine. This latter intramolecular
cyclization is found to be the limiting step
of the process with a yield of 45%, despite
the dropwise addition of the intermediate 3
into the very dilute basic solution to favor
The 1H NMR spectra were recorded in
either deuterated chloroform or acetone-
d6 with a Bruker spectrometer (500 MHz).
Gel permeation chromatography (GPC)
was carried out on a Waters chromatogra-
pher, mounted with Styragel HR 1-4 col-
umns (Waters) and connected to a Waters
410 differential refractometer. THF was
the continuous phase and polystyrenes
of known molecular weights: 500, 2630,
5970, 9100, 37900, 96400 g/mol (Tosoh
Corporation) were used as calibration
standards.
1
uct; H NMR (500 MHz, CDCl3): δ 4.28
(dd, 1H), 1.65–1.9 (br m, 2H), 1.4–1.5 (br m,
2H), 1.25–1.35 (br m, 6H), 0.89 (t, 3H). 13C
NMR (500 MHz, CDCl3): δ 180.00, 70.3,
34.11, 31.59, 28.89, 24.67, 22.53, 14.00.
3-Methyl-6-hexyl-1,4-dioxane-2,5-
dione (4) (referred as monohexyl-
substituted lactide)
10.1 g 2-hydroxyoctanoic acid (63
mmol) and 7.0 ml 2-bromopropionyl bro-
mide (66 mmol) were stirred at 85 °C under
nitrogenfor12h.500mlacetoneand17.6ml
anhydrous triethylamine (126 mmol) were
added to the mixture and the solution was
stirred for 3 h at 60 °C.After filtration of the
triethylammonium bromide salts, acetone
and triethylamine were distilled off and the
resulting mixture was dissolved in 500 ml
Thermal Analysis
Glass transition temperatures (Tg) were
measured with a differential scanning calo-
rimeter (SSC/5200, Seiko Instruments).
Heating was performed at a flow rate of 10
°C/min and the temperature was calibrated
with an indium standard.