PROTOCOL

Synthesis of poly(L-lactide) and polyglycolide by

ring-opening polymerization
Sachiko Kaihara1, Shuichi Matsumura1, Antonios G Mikos2 & John P Fisher3
1Department

of Applied Chemistry, Keio University, Yokohama, 223-8522, Japan. 2Department of Bioengineering, Rice University, Houston, Texas, 77251 USA. 3Fischell
Department of Bioengineering, University of Maryland, College Park, Maryland, 20742 USA. Correspondence should be addressed to J.P.F. (jpfisher@umd.edu).

2007 Nature Publishing Group http://www.nature.com/natureprotocols

Published online 1 November 2007; doi:10.1038/nprot.2007.391

This protocol describes the synthesis of poly(L-lactide) by ring-opening polymerization of L-lactide using tin(II) 2-ethylhexanoate
catalyst as well as the synthesis of polyglycolide by ring-opening polymerization of glycolide. Ring-opening polymerization of cyclic
diesters synthesized from a-hydroxycarboxylic acids gives high-molecular-weight polyester in high yield. Tin(II) 2-ethylhexanoate
catalyst is the most common catalyst for ring-opening polymerization of diesters owing to its high reactivity and low toxicity. Purity
of monomers and the amount of water and alcohol in the reaction system are significant factors for increasing molecular weight and
conversion of polyesters. The molecular weight of the polyesters is also dependent on reaction temperature and reaction time. This
protocol can be completed in 3 d for the synthesis of poly(L-lactide) and 2 d for the synthesis of polyglycolide.

INTRODUCTION
Poly(L-lactide) (PLLA) and polyglycolide (PGA) are biodegradable
polymers that are produced from renewable resources such as
cornstarch and sugar1. These polyesters play important roles not
only as industrial plastics but also as medical biopolymers in
applications such as drug delivery carriers, biomaterial scaffolds and
medical devices. For example, PLLA, PGA and their copolymers have
been investigated as implants for fixation of bones and joints and also
as medical screws and pins for surgery24. Their medical utilization
also includes pharmaceutical applications, such as controlled drug
delivery matrices5,6. The widespread interest in these polyesters as
biological materials may be attributed to their high biocompatibility
and good mechanical properties as well as biodegradability.
The properties of PLLA and PGA, including hydrolysis, biodegradation and mechanical strength, are dependent on their molecular characteristics (see Table 1)7. In particular, polymer
molecular weight and stereochemistry, in the case of the chiral
lactide monomer, have been shown to dramatically affect the
physical properties of the polymer7,8. For example, PLLA polymers
with molecular weight of millions are semicrystalline, whereas
similar-sized poly(D,L-lactide) (PDLLA) polymers are amorphous710 (refer to the works by Lu and Mikos11,12 for a thorough
presentation of the properties of PLLA and PGA). Finally, it should
be noted that crystallinity and thermal properties may also be
controlled by polymer blending13.
There are generally two different routes to produce PLLA and
PGA, either the ring-opening polymerization of cyclic diesters or

the polycondensation of a-hydroxycarboxylic acids10. Ringopening polymerization of cyclic diesters was first suggested by
Carothers et al.14 as a three-step polymerization: (i) polycondensation
of a-hydroxycarboxylic acids, (ii) the synthesis of cyclic diesters by a
thermal unzipping reaction and (3) ring-opening polymerization
of the cyclic diester. Ring-opening polymerization of lactide and
glycolide as well as preparation of these cyclic diesters was then
introduced by Sorensen and Campbell15. The mechanism of each
reaction has been widely investigated and described by many
researchers16.
PLLA and PGA with various terminal groups may be obtained by
ring-opening polymerization with different initiators, such as
1-dodecanol, glycerol and 1,4-butanediol. These initiators affect not
only the conversion rates of the ring-opening polymerization, but also
the properties of corresponding polymers, including degradation rate
and thermal properties17,18. For instance, melting temperatures of
PLLA that were initiated with 1-dodecanol, 1,4-butanediol and
glycerol were 167, 172 and 157 1C, respectively, whereas the
crystallization temperatures were 92, 93 and 101 1C, respectively18.
In addition, the ratio of initiator to monomer affects the molecular
weight of the resulting polymer17. Therefore, as water could be an
initiator for the ring-opening polymerization, it is extremely important to reduce the amount of water in the reactant system as much as
possible to control the molecular weight of the resulting polymer.
Alternatively, it is well known that low-molecular-weight polymers can be produced by the direct polycondensation of lactic acid

TABLE 1 | Mechanical properties of PGA, PLLA and PDLLA7.

Polymer type
(MW)a
Glass transition temperature (1C)
Melting temperature (1C)
Tensile strength (MPa)
Flexural modulus (MPa)
Elongation yield (%)

PGA
50,000
35
210

PLLA
50,000
54
170
28
1,400
3.7

100,000
58
159
50
3,000
2.6

PDLLA
300,000
59
178
48
3,250
1.8

107,000
51

550,000
53

29
1,950
4.0

36
2,350
3.5

aWeight

average molecular weight.

The major column headings denote polymer types, and the minor column headings denote the polymers weight average molecular weight (MW).

NATURE PROTOCOLS | VOL.2 NO.11 | 2007 | 2767

PROTOCOL
O
O
O

Sn(Oct)2

O
O

2007 Nature Publishing Group http://www.nature.com/natureprotocols

Figure 1 | Ring-opening polymerization of L-lactide.

and glycolic acid. The attainment of only low-molecular-weight

polymers is largely due to the difficulty in removing water, the
byproduct during polymerization, which favors depolymerization19. Therefore, ring-opening polymerization of cyclic diesters
using coordination initiators is preferred for the synthesis of
high-molecular-weight polymers. Several types of metal catalysts,
such as aluminum alkoxides and zinc butoxides, are used for ringopening polymerization of cyclic diesters, and the mechanism
of polymerization catalyzed by these catalysts has been widely
investigated2022. The most commonly used catalyst is tin(II)
2-ethylhexanoate (Sn(Oct)2), which is accepted by the Food and
Drug Administration as food additive. Currently, the cyclic diesters,
L-lactide and glycolide, are commercially available worldwide.
Therefore, this protocol introduces the conventional methods to
produce PLLA and PGA from L-lactide and glycolide, respectively.

(Figs. 1 and 2). In particular, we describe here the procedure to

obtain high-molecular-weight polyesters for biomedical applications, including biodegradable fibers and tissue engineering scaffolds. Lactide and glycolide are commercially available. The high
purity of monomer and initiator, and the reduction of water in
the reaction system are keys to successfully obtaining highmolecular-weight polyesters. Finally, for biomedical applications,
it is imperative that all remaining solvents in the polymer solution
must be completely removed after precipitation. Drying under
reduced pressure with heat is the most reasonable method to
remove solvents.
We do note that there is some flexibility in the procedure
described here. For example, lactic acid and glycolic acid can be
used as starting materials; however, the resulting polymers will
likely be of low molecular weight. The catalyst utilized in this
procedure, stannous octanoate (Sn(Oct)2), may be substituted with
other catalysts such as aluminum alkoxide and zinc lactate.

O
O
O

Sn(Oct)2
O

O
n

Experimental design
This protocol describes the synthetic routes of PLLA and PGA by
ring-opening polymerization of L-lactide and glycolide, respectively

Figure 2 | Ring-opening polymerization of glycolide.

MATERIALS
REAGENTS

. Calcium chloride (CaCl2), 497.0%, drying agent (Fluka, cat. no. 21074)
. Chloroform (CHCl3), 99.8%, ACS reagent (Sigma-Aldrich Co., cat. no. 366919)
. Chloroform-d (CDCl3), 100%, contains 0.03% (vol/vol) trimethylsilane
(TMS) (Sigma-Aldrich Co., cat. no. 494275)

. 1-Dodecanol, 498%, ACS reagent (Sigma-Aldrich Co., cat. no. 443816)

. Ethyl acetate, 499.8%, ACS reagent (Sigma-Aldrich Co., cat. no. 319902)
. Glycolide (1,4-dioxane-2,5-dione) (Purac Biochem, PURASORB G)
. Hexafluoroisopropanol (HFIP), 499.8% (Sigma-Aldrich Co., cat. no. 325244)
. Hydrochloric acid (HCl), 37%, ACS reagent (Sigma-Aldrich Co., cat.
no. 320331)

. L-Lactide (3,6-dimethyl-1,4-dioxane-2,5-dione) (Purac Biochem,

PURASORB L)

. Methanol, 499.8%, ACS reagent (Sigma-Aldrich Co., cat. no. 179337)

. Phosphorus pentoxide (P2O5), 498%, ACS reagent (Sigma-Aldrich Co., cat.
no. 298220)

. Sodium chloride (NaCl), 498% (Sigma-Aldrich Co., cat. no. S3014)

. Sodium sulfate (Na2SO4), 498% (Sigma-Aldrich Co., cat. no. 238597)
. Tin(II) 2-ethylhexanoate (stannous octanoate) (Sn(Oct)2), 95% (SigmaAldrich Co., cat. no. S3252)

. Toluene, anhydrous, 99.8% (Sigma-Aldrich Co., cat. no. 244511)

EQUIPMENT

. Three-neck round-bottomed flask

. One-neck round-bottomed flask
. One-way stopcock
. Silicone oil bath
. Vacuum pump
. Magnetic stirring bar
. Condenser
. Thermometer
. Distilling head
. Manometer
. Calcium chloride tube
. Rotary evaporator
. Buchner funnel
. Filter paper
. Glass syringe
. Injection needle
. NMR spectrometer (Bruker)
. Gel permeation chromatography instrument (JASCO)
. Differential scanning calorimeter (Shimadzu)

PROCEDURE
Purification of L-lactide or glycolide
1| Recrystallize L-lactide or glycolide (20 g; L-lactide 0.14 mol, glycolide 0.17 mol) from a minimum amount of toluene
(15 ml for L-lactide; 20 ml for glycolide).
PAUSE POINT Ethyl acetate is an alternative to toluene as a soluble solvent.
2| Filter the precipitated crystal using Buchner funnel.
3| Repeat recrystallization and filtration three times.
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2007 Nature Publishing Group http://www.nature.com/natureprotocols

PAUSE POINT Dry the crystal for 24 h under reduced

pressure (0.01 mm Hg) and keep the crystal over P2O5 in vacuo
at 4 1C before use to avoid the absorption of water.
m CRITICAL STEP Purification of L-lactide is indispensable for
increasing the molecular weight and conversion of the resulting
polymer. Purity of lactide and glycolide can be estimated by
using 1H-NMR. (300 MHz, CDCl3): d 1.66 (d, 6H), 5.09 (q, 2H)
(PLLA), (300 MHz, DMSO-D6): d 4.10 (s, 2H), 4.85 (s, 2H) (PGA)
Preparation of Sn(Oct)2
4| Add Sn(Oct)2 (10 g, 2.5
102 mol) into a one-neck
round-bottomed flask with a magnetic stirring bar equipped
with distilling head and condenser.
5| Place the flask into oil bath at 175 1C.

Condenser
Manometer

Flask
Oil bath

Trap

Pump
CaCl2 tube

6| Distill under reduced pressure (0.1 mm Hg) using vacuum Figure 3 | Apparatus for vacuum distillation.
pump (see Fig. 3).
PAUSE POINT Dry the catalyst for 24 h under reduced pressure (0.01 mm Hg). Store the catalyst at 20 1C in an evacuated,
sealed glass tube.
7| Dissolve Sn(Oct)2 in anhydrous toluene (1.0 M).
8| Perform the synthesis of either PLLA (option A) or PGA (option B).
(A) Synthesis of PLLA
(i) Dry a three-neck round-bottomed flask and one-way stopcock in the oven (100 1C), and set up the apparatus and remove
water from the system by purging with nitrogen (Fig. 4).
(ii) Weigh L-lactide (14.4 g, 0.10 mol) and 1-dodecanol (1.44 mg, 7.7
106 mol) in the flask, vacuum-evacuate and flush
with nitrogen several times.
m CRITICAL STEP The exclusion of water from the system is a critical step for obtaining high-molecular-weight polymer.
(iii) Add toluene solution of Sn(Oct)2 (4.3 mg, 1.1
105 mol) using a syringe with a stainless steel needle into the flask.
! CAUTION Toluene is toxic if inhaled. All work should be performed in a fumehood.
(iv) Distill the toluene under reduced pressure (102 mm Hg) for 30 min and seal the flask.
(v) Condition the flask in a silicone oil bath at 140 1C and shake gently until the monomer is melted and the catalyst is
completely mixed with the molten monomer.
(vi) Stir in a silicone oil bath at 140 1C for 10 h.
m CRITICAL STEP The extent of reaction, as described by an increasing polymer molecular weight distribution, may be
measured by various methods. For example, a simple measure of sample viscosity may be used to qualitatively describe
reaction extent. Gel permeation chromatography and 1H-NMR may be used to describe reaction extent quantitatively.
PAUSE POINT The reaction products may be left overnight, if needed. However, it should be noted that isomerization
may occur. To minimize isomerization, store the products at o4 1C.
(vii) At the end of polymerization, cool down the products to room temperature (25 1C).
(viii) Dissolve the contents in chloroform.
! CAUTION Chloroform is an irritant and is potentially
harmful. Proper personal safety equipment should be
worn when handling chloroform.
(ix) Precipitate the polymer by adding the solution into
an excess amount of methanol.
(x) Filter the white precipitate using the Buchner funnel.
Flask
(xi) Repeat Steps (viiix) three times.
PAUSE POINT Dry the product under vacuum at 40 1C
Oil bath
until a constant weight is maintained. The drying time
should last at least 24 h, but may be longer.
(B) Synthesis of PGA
(i) Dry a three-neck round-bottomed flask and purge with
nitrogen.
Trap
(ii) Weigh glycolide (11.6 g, 0.10 mol) and 1-dodecanol
(1.16 mg, 6.2
106 mol), vacuum-evacuate and flush
with nitrogen several times.
Figure 4 | Apparatus for ring-opening polymerization.
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2007 Nature Publishing Group http://www.nature.com/natureprotocols

(iii) Add toluene solution of Sn(Oct)2 (3.48 mg, 8.6
106 mol) using a syringe with a stainless steel needle into the flask.
(iv) Distill the toluene under reduced pressure (102 mm Hg) for 30 min and seal the flask.
! CAUTION Be careful not to distill glycolide through the vacuum line under reduced pressure. In particular, do not warm
up the reactant above room temperature before or during vacuum procedure.
(v) Put the flask into silicone oil bath, pass argon over the surface of the mixture and stir at 195 1C.
(vi) After 10 min, raise the temperature to 230 1C during a 20-min period.
(vii) Stir at 230 1C for 30 min.
(viii) Reflux the product in ethyl acetate to extract the residual monomer.
PAUSE POINT Dry the product for 24 h under vacuum at 40 1C and finally grind it.
Determination of thermal properties and molecular weight of PLLA and PGA
9| Determine the thermal properties and molecular weight using either differential scanning calorimetry (option A) or gel
permeation chromatography (option B).
(A) Differential scanning calorimetry
(i) Weigh 12 mg of each polymer sample on an aluminum pan. Operate at a scan speed of 10 1C min1.
(B) Gel permeation chromatography
(i) Measure the molecular weight at 35 1C using a GPC column (K-804, 8 mm
300 mm, Shodex) at a flow rate of
1 ml min1 using chloroform and hexafluoroisopropanol as the eluents for PLLA and PGA, respectively. In the case of
refractive index detector, measure the molecular weight based on a calibration curve generated from polystyrene
standards (Mw 2.33
105, 1.10
105, 5.0
104, 1.75
104, 9.0
103, 2.2
103, 9.06
102) as PLLA or
PGA standards might be difficult to obtain. In the case of a light scattering detector, the molecular weight may be
obtained directly.

TIMING
Preparation: Steps 13, 24 h; Steps 47, 24 h
Synthesis of PLLA: Steps 8A(iv), 1 h; Step 8A(vi), 10 h; Steps 8A(viixi), 3 h
Synthesis of PGA: Steps 8B(iiv), 2 h; Steps 8B(vvii), 2 h; Step 8B(viii), 5 h
Determination of thermal properties and molecular weight: Step 9A, 2h; Step 9B, 3h
? TROUBLESHOOTING
Troubleshooting advice can be found in Table 2.
TABLE 2 | Troubleshooting table.
Problem
Low molecular weight

Solution
Repeat recrystallization of monomers
Lower the reaction temperature
Increase the reaction time
Repeat the evacuation and nitrogen flush cycle

Low yield of polymer

Increase the volume of methanol for recrystallization

Low purity of polymer

Repeat precipitation of polymers

a
ANTICIPATED RESULTS
Typical yields
Typical isolated yields are 495% for both PLLA and PGA
(Fig. 5).
PLLA: 1H NMR (300 MHz, CDCl3): d 1.55 (d, J7.1 Hz, 3H),
4.36 (q, J6.96 Hz, 1H), 5.20 (q, J6.96 Hz, 1H
(terminal)). 13C NMR (75 MHz, CDCl3): d 16.6, 68.9, 169.5.
Molecular weight: 1.0
1051.1
105.
PGA: 1H NMR (300 MHz, DMSO-D6): d 4.10 (s, 2H
(terminal)), 4.85 (s, 2H). 13C NMR (75 MHz, DMSO-D6):
d 60.4, 166.0. Molecular weight: 1.0
1051.0
106.
2770 | VOL.2 NO.11 | 2007 | NATURE PROTOCOLS

Figure 5 | Photographs of polymer products L-lactide and PLLA after

re-precipitation. (a) L-Lactide. (b) PLLA.

PROTOCOL
ACKNOWLEDGMENTS This work was supported by a Grant-in-Aid for General
Scientific Research and by a Grant-in-Aid for the 21st Century COE Program KEIO
LCC from the Ministry of Education, Culture, Sports, Science, and Technology,
Japan. This work was also supported by a US National Institutes of Health grant to
A.G.M. (R01 DE15164) as well as by the US National Science Foundation through a
CAREER Award to J.P.F. (no. 0448684) and the Arthritis Foundation through an
Arthritis Investigator Award to J.P.F.

2007 Nature Publishing Group http://www.nature.com/natureprotocols

Published online at http://www.natureprotocols.com

Reprints and permissions information is available online at http://npg.nature.com/
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