Journal of Bioactive and

Compatible Polymers
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An Investigation of Poly(lactic acid) Degradation

Xichen Zhang, Urs P. Wyss, David Pichora and Mattheus F.A. Goosen
Journal of Bioactive and Compatible Polymers 1994 9: 80
DOI: 10.1177/088391159400900105

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 Investigation of
An
Poly(lactic acid) Degradation
XICHEN ZHANG,* URS P WYSS,** DAVID PICHORA†
AND MATTHEUS F. A. GOOSEN* &dag er;&dag er;
Queen’s University
Kingston, Ontario, Canada K7L 3N6

ABSTRACT: To elucidate the degradation mechanism of poly(lactic acid), the

decrease in the intrinsic viscosity of poly(D,L-lactide) in a homogeneous water/
acetone solution was investigated. The hydrolysis of poly(D,L-lactic acid) in
water/acetone solution can be catalyzed by protons. The molecular weight
degradation of solid poly(D,L-lactic acid) in water was primarily affected by the
degree of polymer purity. Polymerization conditions such as initiator concen-
tration, temperature and time did not have an obvious effect on the molecular
weight degradation. In the case of polymer samples with low purity (i.e.,
directly polymerized or containing solvent or oligomer), degradation was ini-
tially very rapid. On the other hand, initial degradation of purified polymer
was very slow before accelerating.

INTRODUCTION

oly(lactic acid) (PLA) has been widely used in controlled drug de-
re-
P lease and tissue fixation due to its high biocompatibility and
gradability. Understanding the polymer degradation mechanism is im-
portant so that the degradation rate can be controlled [1,2]. Poly(lactic
acid) degrades through hydrolysis of the backbone ester groups, and
this hydrolysis is thought to be auto-catalyzed by the polymer carbox-
ylic acid end groups. The process follows a first order kinetics expres-
sion :

*Department of Chemical Engineering.

**Department of Mechanical Engineering.
1’Department of Surgery.
fitAuthor to whom correspondence should be addressed.

80 Journal of BIOACTIVE AND COMPATIBLE POLYMERS, Vol. 9- January 1994

0883-9115/94/01 0080-21 $6.00/0

@ 1994 Technomic Publishing Co., Inc.

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 81

where M, and Mo represent polymer molecular weight at timet and

zero, respectively [3]. This equation represents the early degradation
behavior of poly(lactic acid), poly(E-caprolactone) and their copolymers
very well [4,5]. However, the hydrolysis of polyesters is normally cata-
lyzed by protons (H+) rather than associated carboxylic acids [6]. It has
been argued [7] that since the carboxylic acid is unlikely to be disso-
ciated in the hydrophobic polyester domain, an associated carboxylic
acid catalyzing mechanism is possible. To clarify this ambiguity and to
avoid the complexity of a heterogeneous reaction of solid lactide in
water, the degradation of poly(D,L-lactic acid) in a homogeneous reac-
tion solution was employed. The reaction system consisted of poly(D,L-
lactic acid)/water/acetone with or without the presence of HCI or acetic
acid. PDLLA dissolves in acetone in the presence of a small amount of
water and acid.
Although this polymer degradation is a simple hydrolysis, the
degradation rate can be affected by many factors due to the complexity
of the solid-liquid reaction system. Principally, the polymer degrada-
tion rate is determined by polymer reactivity with water and ac-
cessibility of the ester groups to water and to catalysts (carboxylic acid
end groups). Any factor affecting the reactivity and the accessibility
will affect the polymer degradation rate. These factors might include
polymer chemical structure, molecular weight, molecular weight dis-
tribution, and morphology in addition to the water diffusion rate into
the polymer and the water content in the polymer [1]. Although many
studies on poly(lactic acid) biodegradation exist in the literature, it is
still not clear which factors are critical because of the lack of adequate
polymer characterization.
The objective of this study was to identify critical factors affecting the
poly(lactic acid) degradation rate for the purpose of obtaining practical
guidelines that can be used to control polymer degradation. Poly(lactic
acid) degradation data in the literature was also summarized and com-
pared to our results.
EXPERIMENTAL

Polymer Synthesis

Poly(lactic acid) was synthesized by an established procedure [8,9].

Briefly, the monomer and initiator (stannous octoate) were loaded into
a glass reaction ampoule. The ampoule was sealed under high vacuum

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82

and the polymerization was carried out at 100-130 ° C (Table 1). The
resulting polymer was dissolved in chloroform, precipitated in ethanol,
and vacuum dried. The poly(D,L-lactic acid) (PDLLA) and poly(L-lactic
acid) (PLLA) molecular weights were calculated from the intrinsic vis-
cosities [~] in chloroform at 25 ° C using the Mark-Houwink equation
([~] = KM,,; for PDLLA: a 0.75, K 3.64 x 10-4 dl/g; for PLLA:
= =

a = 0.73, K = 5.45 x 10-4 dl/g) [7].

The D,L-lactic acid (DLLA) oligomer was synthesized by a poly-
condensation procedure. D,L-Lactic acid was added to a flask without
any catalyst and heated under nitrogen at 180-200 ° C. The water gen-
erated in the reaction was removed by interval nitrogen purging and
vacuum. A mixture of high molecular weight PDLLA and DLLA oli-

gomer was obtained by dissolving the materials in acetone followed by

removal of the solvent.

Poly(D,L-lactic acid) Degradation in Acetone/H20 Solution

Poly(D,L-lactic acid) was dissolved in acetone, and different amounts

of water, HCI or acetic acid were added to the polymer solution. The
decreasing intrinsic viscosity of the reaction solution was measured.
Solid Polymer Degradation in Water

Poly(lactic acid) films were manufactured either by solution casting

from chloroform or by melt pressing at 100-180 ° C/500 psi (Table 1).
The polymer films and directly polymerized poly(D,L-lactic acid)
cylinders (i.e., unpurified polymer) were incubated in distilled water at
37 ° C. The water uptake was measured by polymer wet weight gain.
Polymer molecular weight degradation was assessed by measuring the
decrease in intrinsic viscosity. The PDLLA film (width 11 t 1 mm,
thickness 0.5 db 0.15 mm) tensile strength was measured using an In-
stron instrument, Model 1122 (VACS Ltd., Toronto) at a drawing speed
of 10 mm/min and with a cross head distance of 20 mm.

RESULTS AND DISCUSSION

PDLLA Degradation in Water/Acetone Solution

In the absence of acid, the intrinsic viscosity of the polymer dissolved

in water/acetone did not decrease during a 400 h testing period (Table
2). Neither a low HCI concentration ([HCl]/[ester] 0.001) nor high =

acetic acid concentration ([A,c]/[ester] 0.1) accelerate the polymer

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86

hydrolysis rate. However, a dramatic catalytic effect by HCI on the

polymer degradation rate, was observed at an [HC1]/[ester] molar ratio
in the range 0.01-0.1. The catalytic effect by acetic acid was only
observed at high concentrations ([Ac]/[ester] 10). The strong cata-=

lytic effect of HCI and weak catalytic effect of acetic acid suggest that
polymer hydrolysis might be catalyzed by a proton instead of an asso-
ciated carboxylic acid. In water, HCI dissociates completely, while
acetic acid remains mostly in the associated form. The dissociation con-
stant of acetic acid in water at 37 ° C is 1.718 x 10-5 [11] so the proton
concentration is only [H+l = 4.1 x 10-3 [Ac]° 5. Although the dissocia-
tion behavior of HCl and acetic acid in an H20/acetone mixture must be
different from that in pure water (likely smaller), they should be simi-
lar.
If the [ester], [H,01 and [H+] concentrations are considered constant in
each case, then the following kinetic equation for uncatalyzed hydroly-
sis [12] can be used to describe the solution degradation:

where M, and Mo are the polymer molecular weight at timet and zero,
respectively, and k is the rate constant. In practice, polymer molecular
weight is often approximated from the viscosity average molecular
weight, which can be calculated from the intrinsic viscosity employing
the Mark-Houwink equation:

where a and K are Mark-Houwink parameters. The intrinsic viscos-

ities of PDLLA in acetone with Mv of 3.50 x 104, 3.61 x 104,
8.56 x 104, and 33.95 x 104 were measured at 0.771, 0.666, 1.26, and
2.52 dl/g, respectively. Linear regression of the log form of Equation (3),
using the above data, gave an a of 0.59 with a correlation coefficient of
0.999. Combining Equation (2) and Equation (3), gives:

Equation (4) describes PDLLA degradation in acetone quite well

(Figure 1). The rate constant in Equation (4) increased with increasing
[bI+]. Surprisingly, no significant effect of water concentration on the
degradation rate was observed in our experiments (Table 2).

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 87

Figure 1. Effect of proton concentration of PDLLA hydrolysis in homogeneous polymer/

water/acetone solution.

Degradation of Polylactide in Water

The degradation behavior of solid polymers can be divided into two
types. One type obeys first order kinetics [Equation (1)] immediately
after contact with water (Figure 2). The other degradation type has a
lag phase before first order degradation starts (Figure 3). To help
understand the results, the polymer synthesis and processing history
for each degradation line in Figures 2 and 3 have been summarized in
Table 1. The samples made from unpurified polymer (as-polymerized)
or purified polymer with addition of D,L-lactic acid oligomer, and the

samples manufactured by solvent casting (regardless of whether the

polymer was purified) all underwent the first degradation type. On the
other hand, samples made from purified polymer (i.e., dissolution/
precipitation purification) and melt processed underwent the second
degradation type. In our experimental range, the purification
(recrystallization) of monomer before polymerization, polymerization
conditions (initiator concentration, polymerization time and tempera-
ture), polymer molecular weight, and thermal degradation [8] of
poly(lactic acid) in the melt processing did not affect the type of
degradation. This indicates that degradation is primarily affected by
polymer chain flexibility in the sample. The presence of low molecular
weight substances and solvent makes the polymer main chain more
flexible, which affects degradation (the first type). However, the move-

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88

Figure 2. Molecular weight loss of unpurified poly(lactic acid) in water (see Table 1 for
details).

ment of long chains in the purified polymer, with fewer small mole-
cules, is restricted. Chain restriction has to be relaxed, perhaps
more

by water molecules, before significant degradation occurs. This lag

phase results in the second degradation type. Hot press and melt injec-
tion processes help chain fixation, a phenomenon called chain freezing
in the literature [13]. Chain restriction is more pronounced in the case
of semicrystalline polymer [e.g., poly(L-lactic acid)].
The degradation rate in the first order degradation phase varied from
0.0183 day-’ to 0.0447 day-’ (Table 1). The difference between the rate
constants could not be addressed to a particular factor due to the large
variance. The molecular weight decrease leveled off after the initial
rapid decrease (Figure 3, samples 13 and 14). This may have been due

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 89

to the possibility that carboxylic acid groups started to diffuse out of

the polymer. This would decrease the catalytic effect [1], which in turn
would decrease the polymer degradation rate.
Water uptake is a sensitive indicator of the hydrophilic impurities in
a polymer. The impure films made from the nonprecipitated polymers
absorbed water quickly and reached a constant around 50% w/w within
10 days (Figure 4, lines 4, 5, 6). The films turned from transparent to
white during the first day in water. However, films made from purified
polymer absorbed water more slowly (Figure 4, lines 13-16). They took
up about 1.5% w/w water almost immediately (perhaps by filling the
cavities in the films), then remained constant for a period of time (one
to two months), and then started taking up water again. The films
became white at about 8% w/w water uptake.

Figure 3. Molecular weight loss of purified poly(lactic acid) in water (see Table 1 for
details).

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90

Figure 4. Water uptake by PLA (see Table 1 for details).

The water uptake behavior of larger samples (the cylinders) was dif-
ferent from that of small samples (the films) since water uptake is a dif-
fusion process. The as-polymerized PDLLA cylinder absorbed 1% water
immediately. Water absorption then gradually increased; at day 8 it
rapidly increased (Figure 4, line 3). A white skin and a more transpar-
ent core formed for the as-polymerized PDLLA cylinder were observed.
These phenomena were first identified by Li et al. [14]. They found that
due to the rapid loss (by diffusion) of degraded small molecules from the
outer region of the sample, the inner core degraded faster.
Molecular weight degradation, water uptake, tensile strength and
change in elongation data for a melt pressed film sample made from a
purified PDLLA sample are summarized in Figure 5. The tensile

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 91

strength dropped quickly, even without significant polymer molecular

weight loss. Elongation initially increased and then decreased; this in-
dicates a significant plasticization effect by water on PDLLA. After the
polymer degraded to a certain level, this plasticization was ineffective.
However, plasticization may not be significant in the case of PLLA due
to the high crystallinity of this polymer.
In order to compare our results with those obtained by others, the
molecular weight loss, mechanical strength loss, and mass loss data for
PLLA and PDLLA in the literature were summarized (Figures 6-8,
Table 3). The molecular weight loss and the mechanical strength loss of

Figure 5. Molecular weight loss, water uptake, tensile strength loss and elongation of a
melt pressed film made from purified PDLLA (Mv of 4.8 x 10B polymerization conditions
were the same as sample 2 in Table 1).

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92

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Figure 6. Literature summary of poly(lactic acid) molecular weight loss (see Table 3 for
details).

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 97

the as-polymerized samples were much faster than those for the puri-
fied samples (normally precipitated polymer) which is similar to our ex-
perimental findings. Similarly, degradation of the as-polymerized
samples was initially rapid and then slowed down, while degradation of
the purified samples went through a lag phase and then increased. The
molecular weight, strength and mass loss by PDLLA was much faster
than by PLLA (Figures 6-8, Table 3). Polymer mass loss depended on
the initial molecular weight, degradation rate and sample dimension.
For a PLLA sample of only a few millimeters in thickness, for example,
total mass loss could take two to three years. The degradation data for
the purified PLLA were less consistent than for the as-polymerized
PLLA, perhaps due to the requirement of additional polymer process-
ing after its purification.
Based on our experimental results as well as the literature survey,
the purity of the polymer sample is the most critical factor affecting the

Figure 7. Literature summary of poly(lactic acid) mechanical strength loss (see Table 3
for details).

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98

Figure 8. Literature summary of poly(lactic acid) mass loss (see Table 3 for details).

degradation rate. The effects of other factors, such as degradation en-

vironment, sample shape and area/volume ratio, could not be distin-
guished.
CONCLUSIONS

The degradation of poly(lactic acid) appears to be proton catalyzed.

Our study and review of the literature show that polymer purity is the
most critical factor affecting the hydrolytic degradation of poly(lactic
acid). For poly(lactic acid) with a low degree of purity (as-polymerized
polymer or containing low molecular weight components), degradation
was initially very rapid. However, for polymer samples with a high

degree of purity (melt processed samples from precipitated polymers),

degradation went through a lag phase before rapid degradation oc-
curred. By controlling the impurity content in the polymer, the
degradation of poly(lactic acid) can be deterred.

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 99

ACKNOWLEDGEMENT

The authors are grateful for financial support from the Ontario Cen-
tre for Materials Research.

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