Biocompatible Catalysts for Lactide Polymerization - Catalyst Activity, Racemization Effect, and Optimization of the Polymerization Based on Design of Experiments

Article abstract of DOI:10.1021/acs.oprd.0c00149

An original synthesis of Ca, Mg, and Zn 2-ethylhexanoate (octoate) obtained by reaction between metallic powder with 2-ethylhexanoic acid was achieved. The activities of obtaining biocompatible catalysts of lactide polymerization were tested. The most act

Full text of DOI:10.1021/acs.oprd.0c00149

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Full Paper
Biocompatible catalysts for lactide polymerization –
catalyst activity, racemization effect and optimization
of the polymerization based-on Design of Experiments.
Agnieszka Gadomska-Gajadhur, and Pawe# Ru#kowski
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00149 • Publication Date (Web): 13 Jul 2020
Downloaded from pubs.acs.org on July 14, 2020
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Biocompatible catalysts for lactide
polymerization – catalyst activity,
racemization effect and optimization of the
polymerization based-on Design of
Experiments.
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Agnieszka Gadomska-Gajadhur and Paweł Ruśkowski*
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3 st., 00-664
Warsaw, Poland.
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Table of Contents
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ABSTRACT: An original synthesis of Ca, Mg and Zn 2-ethylhexanoate (octoate) obtained
by reaction between metallic powder with 2-ethylhexanoic acid was achieved. The
activities of obtaining biocompatible catalysts of lactide polymerization were tested. The
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most active catalyst was zinc 2-ethylhexanoate (ZnOct ), and the lowest activity had
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calcium 2-ethylhexanoate (CaOct ). The ROP process was successfully optimized by
2
using the design of the experiment. Polylactide with M =82.3 kg/mol with lactide
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conversion up to 85% and 8% content of D-lactic acid has been obtained. Thus obtained
polylactides can be used in medical and pharmaceutical devices.
KEYWORDS: PLA, racemization, medical devices, DOE, scale-up
INTRODUCTION
Polylactide is a "double green" polymer with high application potential.1,2 Raw materials
3
for its production can be obtained from renewable resources. After using the product, it
4
can be composted, where it decomposes into non-toxic products (CO and H O). Non-
2
2
toxic and biocompatible PLA can be used in regenerative medicine for damaged tissues.
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Also, PLA has found many applications: packaging materials,1,5 textiles, composites.
6
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Medicine,7,8 and pharmacy9,10 are continually looking for new applications for polylactide.
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Researchers focused on developing new forms of drug delivery systems (DDS) and
developing materials for regenerative medicine.11,12,13,14,15
The monomer in PLA is lactic acid (LAc) (Scheme. 1). It is a weak, water-soluble organic
acid with an asymmetric carbon atom.16 Lactic acid may exist in the form of two
enantiomers: D-(-)-LAc or L-(+)- LAc. L-(+)- LAc is present in living organisms as a
product of various metabolic changes.17 Lactic acid can be obtained as a result of
chemical synthesis and biotechnological methods.18,19
Scheme 1. Synthesis of chiral lactic acid and chiral lactide
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biotechnological method
CH3
H C
O
O
3
cyclization
fermentation
sugar
O
HO
O
H
OH
O
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CH3
L-(+)-lactic acid
L,L-lactide
CH3
H C
O
3
chemical method
O
HO
O
CH3
H
OH
O
O
H C
O
3
O
+
L-(+)-lactic acid
1
. KCN/H /EtOH
cyclization
O
CH3
O
+
2
. H O/H
2
O
H C
L,L-lactide
3
H C
O
CH3
acetone
3
CH3
HO
O
meso-lactide
H
OH
O
O
D-(-)-lactic acid
O
CH3
D,D-lactide
In chemical synthesis, a racemic LAc mixture is obtained. Biotechnologically, however,
both optically active enantiomers can be selectively obtained as a result of bacterial (e.g.
using the Lactobacillus strain20,21,22) fermentation of starch and other carbohydrates
derived from corn, sugar beet or potatoes.23
The properties of PLA depend on the stereochemical composition of the repeat units
24
and their distribution along the chain. Homochiral PLA (PLLA or PDLA) (Fig. 1) is an
isotactic, stereoregular and semicrystalline polymer (degree of crystallization up to 40%),
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with T 55–65 °C and T 170–183 °C. Atactic PLA is made of heterochiral PLDLA units.
g
m
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It is an amorphous polymer with T = 59 °C, without melting point. A mixture of
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homochiral, isotactic PLLA and PDLA chains creates stereocomplexes with a melting
point of approx. 230 °C.27,28
Figure 1. Chemical structure of polylactide, stereochemistry and properties
Mechanical properties characterize materials made of PLA. It can be a soft and flexible
or hard and durable plastics.29 For homochiral PLA, as the average molar mass
increases, the flexural strength increases, and the tensile strength does not change.30
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However, as the PLDLA average molar mass increases, the flexural and tensile strength
increases.31
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Polylactide with strictly defined chirality can be obtained using optically active catalysts or
mixtures of D,D-lactide and L,L-lactide with defined stoichiometry.32 The cost of
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purchasing D,D-lactide is about twice as high as L,L-lactide. The price of meso-lactide
is challenging to determine because there are no suppliers of this raw material.34
Therefore, many groups are working on catalysts that racemize lactide in situ in
polymerization.35
36
Direct lactic acid condensation on tin or zinc oxide leads to PLA under 5 kg/mol. High
molecular weight PLA is obtained by ring-opening polymerization (ROP).37 The most
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popular catalyst is tin(II) 2-ethylhexanoate (SnOct ). The high molecular weight polymer
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(M > 100 kg/mol) is obtained with high lactide conversion (> 95%).
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Scheme 2. The synthesis of polylactide with tin(II) octoate.
O
O
Oct Sn
2
n/2
H
O
n
O
O
H
O
O
1
2
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The production of PLA with tin(II) catalysts41,42, disqualify such obtained material from
medicinal applications. Acceptable content of tin(II) residue in medical devices should not
exceed 20 ppm of tin.43 The practical exclusion of tin content in medical devices is a
premise to research the search for new biocompatible catalysts for lactide
polymerization.44,45,46,47
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In the synthesis of medical PLA, it is recommended to use zirconium48 and
titanium49,50,51 catalysts. Zirconium and titanium are used to production of bone implants,
so they should also be non-toxic to humans in other applications. However, it has been
found that some people may have an allergic effect. Zr and Ti catalysts are more
expensive than the commonly used SnOct , which increases the cost of PLA production.
2
The latest trend in catalyst synthesis is the use of molecules found in metabolic
pathways, i.e. magnesium,52,53 zinc54,55,56,57,58,59,60 and calcium.61,62 To date, scientists
have developed dozens of catalysts based on zinc. 54,55,56,57,58,59,60 Unfortunately their use
leads to low molecular weight PLA (M <15 kg/mol). Less scientific work concerns
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catalysts of magnesium and calcium.52,53 Polymerizations catalyzed with Ca and Mg salts
have a long time of reaction (1–4 days) and polymer molar mass under 13 kg/mol.
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Our research aimed to find new non-toxic catalysts for lactide polymerization. The next
step was examined catalysts activity and determine optimal reaction conditions.43
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Additionally checking whether racemization of the chiral center in lactic acid occurs due
to the use of strongly basic metals in catalysts.
Presently the most effective ROP catalyst is SnOct . We tried to obtain its magnesium,
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zinc and calcium analogue MOct (M is metal).
2
Several methods can obtain magnesium (calcium or zinc) octoate (4). The first method
is the reaction between 2-ethylhexanoic acid (3) and a metal oxide.63,64 The water formed
in the reaction is azeotropically separated. The second method is the reaction between
metal chloride65,66 and 2-ethylhexanoic acid (3). In this reaction, hydrogen chloride is
formed in addition to the desired catalyst. The presence of hydrogen chloride is
unfavorable due to its strong corrosive effect on steel apparatus.
We used the design of experiments to optimize process conditions. Three variables in
the rotatable factorial plan were examined. We tested the significance of the equation
coefficients with the Student's test. The MS Solver add-on predicted the optimal
conditions of polymerization.67
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EXPERIMENTAL SECTION
All solvents (toluene, dichloromethane) and other reagents (magnesium, zinc, calcium)
were used without any purification.
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L,L-lactide (Boehringer Company) with high purity >99.5%, water content <80 ppm and
free acids content under 0.3 mmol/kg was used. IR spectra were measured using a
1
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BRUKER ALPHA II Platinum ATR spectrometer (in ATR technics). H or C NMR spectra
were measured using a Mercury-400BB spectrometer (400 MHz). Elemental analysis was
measured by Perkin Elmer, model PE Seria II CHNS/O. A gel permeation
chromatography measured molecular weights of PLA samples. The apparatus UltiMate
3000 Dionex, with refractometric detector RIn-101 Shodex and with two Jordi Gel DVB
Mixed Bed columns was used. Conversion of lactide was predicted using the calibration
curve method.
The specific rotation of the product was measured with a polAAr 32 automatic
polarimeter.
The content of D centers in the PLA chain was calculated from the formula:
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[
훼] + 훼w
%
퐷 =
∙ 100%
2
∙ 훼w
where:% D - the percentage of centers -D; [α] - specific rotation of the tested polymer
αw - specific rotation of poly-D-lactide (+161.0 °)
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Synthesis of calcium 2-ethylhexanoate (CaOct , 4a). 2-ethylhexanoic acid (11 mL, 10
2
g, (0.07 mol)), pellets of calcium (1.40 g, 0.035 mol, the particle size of calcium <5 mm)
and toluene (70 mL) were agitated (200 rpm) and heated under reflux for 24 hours.
Unreacted calcium was filtered out from the hot solution. Product was filtered at room
temperature and washed with toluene (15 mL).
Product was obtained with 64% yields (7.3 g, 0.022 mol) and 95.3% purity.47
–
1
1
CaOct : white solid; IR (ATR, cm ): 2962, 2936, 1685, 1561; H NMR (400 MHz, DMSO-
2
d6) δ/ppm: 0.82 (2t, 6H) 1.22 (m, 4H) 1.28 (m, 2H) 1.45 (m, 2H) 1.87 (s, 1H); elemental
analysis (%): cal. C 58.86; H 9.26; anal. C 59.87; H 9.22.
Synthesis of magnesium 2-ethylhexanoate (MgOct , 4b). 2-ethylhexanoic acid (22 mL,
2
2
0 g, (0.14 mol), powdered magnesium (1.68 g, 0.07 mol, the particle size of magnesium
5 µm) and toluene (100 mL) were agitated (200 rpm) and heated under reflux for 20
<
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hours. Unreacted magnesium was filtered out from the hot solution. Product was filtered
at room temperature and washed with toluene (15 mL).
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Product was obtained with 80% yields (17.4 g, 0.11 mol) and 99.8% purity.68
–1
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MgOct : yellow solid; IR (ATR, cm ): 2960, 2934, 1692, 1603; H NMR (400 MHz,
2
13
DMSO-d6) δ/ppm: 0.84 (m, 6H) 1.26 (m, 4H) 1.59 (m, 4H) 1.89 (m, 1H); C NMR (100
MHz, DMSO-d6) δ/ppm: 12.1; 14.0; 22.8; 25.4; 29.7; 31.8; 47.6; 183.9; elemental analysis
(%): cal. C 61.8; H 9.73; anal. C 61.5; H 9.71.
Synthesis of zinc 2-ethylhexanoate (ZnOct , 4c). 2-ethylhexanoic acid (11 mL, 10 g,
2
(0.07 mol)), powder of zinc (2.246 g, 0.034 mol, the particle size of zinc <1 µm) and
toluene (70 mL) were agitated (200 rpm) and heated under reflux for 8 h. Unreacted zinc
was filtered out from the hot solution. Product was filtered at room temperature and
washed with toluene (15 mL).
Product was obtained with 87% yields (10.4 g, 0.03 mol) and 99.5% purity.47
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–
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ZnOct : transparent syrup; IR (ATR, cm ): 2962, 2933, 1628, 1592; H NMR (400 MHz,
2
DMSO-d6) δ/ppm: 0.80 (m, 6H) 1.23 (m, 4H) 1.35 (m, 2H) 1.45 (m, 2H) 2.02 (dq, 1H);
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
4
4
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4
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4
4
4
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5
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5
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6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
elemental analysis (%): cal. C 54.62; H 8.59; anal. C 54.63; H 8.62.
Polymerization of L-lactide. L-lactide (8.64 g, 0.06 mol) was melted in an argon
atmosphere with magnetic stirring (160 rpm) in a temperature range from 120 °C to 200
°C (start of polymerization). 0.06–0.7 mL of 0.12 M solution of catalyst (MgOct , CaOct ,
2
2
ZnOct )in CH Cl was added (0.05–1.5 % catalyst/lactide ratio). reactions were carried
2
2
2
mol.
out in t = 1–32 h. The reaction products were cooled down to room temperature in an
argon atmosphere and analyzed. Polylactides were obtained with the conversion of
lactide 2–98.0% and M 1.2–34.1 kg/mol, DI 1.4–2.4, %D 0–13%.
w
–1
1
PLA: white or yellow solid; IR (ATR, cm ): 1749, 1181, 868; H NMR (400 MHz, CDCl )
3
13
δ/ppm: 1.54 (d, 3H) 5.18 (q, 1H); C NMR (100 MHz, CDCl ) δ/ppm: 16.7; 20.5, 52.3,
3
69.0, 170.3
RESULTS AND DISCUSSION
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6
Catalyst’s synthesis The catalyst synthesis was carried out in the direct reaction of an
acid (3) with metal (Scheme 3). The merit of this method is the lower price of metal than
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
its oxide or chloride. The second reaction product is hydrogen, which is removable from
the reaction mixture.47
Scheme 3. Obtaining of calcium, magnesium and zinc 2-ethylhexanoate
O


O
2
M
2+
+
M
OH
toluene
-
+
H2
O
2
3
4
M=Ca (a); Mg (b); Zn (c)
The reaction between acid 3 with metal was carried out in reflux of toluene. The
substrates were mixed using a magnetic stirrer for 8–24 h (yield 64–87%). The viscosity
of the reaction mixture acid 3 to metal in molar ratio 2:1 was too high. To reduce them
was necessary to add an appropriate volume of toluene. This treatment allowed for better
mixing of the reaction mixture in the final stage of the process. The unreacted metal
particles were selectively separated by hot filtration. The yellow product is crystallized
from the toluene solution at room temperature. Then it could be separated by subsequent
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filtration. The last step was washing a product with toluene and drying at room
temperature. The catalyst was obtained with sufficient good purity. The most importantly
was low content of water (<400 ppm). The presence of water in the catalyst is
disadvantageous because it cannot be used for ring-opening polymerization.
Table 1. Results of synthesis of calcium, magnesium and zinc octoate
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
-
time (h)
yields (%)
purity (%)
water content (ppm)
ethylheksanoate
zinc
8
87.0
80.0
64.0
99.5
99.8
95.3
350
280
300
magnesium
calcium
20
24
Catalysts activity in lactide polymerization.
L-LD polymerization was provided out at 200 °C for 24 h with 0.05%mol catalyst (Fig.
.). The lowest LD conversion was obtained with a calcium catalyst (58%). The
2
conversion at the same high level (92%) was achieved in the case of magnesium (91.5%)
and zinc (92.8%) catalysts. The lowest molecular weight, 19.5 kg/mol, was obtained
against CaOct . The polylactide obtained against MgOct had an average molar mass of
2
2
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about 31 kg/mol. The highest molar mass (64 kg/mol) was obtained in a ZnOct catalyzed
2
reaction.
0
1
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9
0
1
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3
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9
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8
9
0
1
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3
4
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9
0
80
100
90
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6
0
0
8
7
6
0
0
0
50
4
3
2
0
0
0
50
40
3
2
1
0
0
0
0
10
0
CaOct2
MgOct2
ZnOct2
Figure 2. The influence of catalyst on lactide conversion and molecular weight
Racemization of lactide in ROP.
Two methods determined the degree of racemization of lactic acid in polylactide. The
signal surface ratio of 169.3 ppm (heterochiral PLA) to 169.5 ppm (homochiral PLA) was
13
determined in the C NMR spectrum (Figure 3).
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GADgd26c
0.30
0
.25
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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5
5
5
6
0
1
2
3
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5
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7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0.20
0
.15
0.10
0
.05
0
-0.05
-0.10
1
71.0 170.5 170.0 169.5 169.0 168.5
1
3
Figure 3. The fragment of C NMR spectrum of polylactides obtained against SnOct
2
(blue), CaOct (green), MgOct (red) (169.3 ppm – PDLLA, 169.5 ppm - PLLA)
2
2
1
3
Table 2. The degree of racemization of lactic acid in PLA determined by C NMR and
specific rotation measurement
RACEMIZATION DEGREE OF LACTIC ACID, %
CATALYST
13C NMR
specific rotation
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SnOct2
CaOct2
MgOct2
ZnOct2
0
0
32.0
20.3
14.5
31.9
20.8
13.9
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2
3
4
5
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8
9
0
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2
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3
4
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9
0
1
2
3
4
5
6
7
8
9
0
Optimization of L,L-lactide polymerization. High conversion of lactide in PLA is
necessary for the material to be used in medicine. When residual lactide concentration in
PLA is high, additional steps to remove it are required. This prolongs the process and
increases its cost.69,70,71 The molecular weight of PLA significantly affects the potential
application. The higher M PLA is used for implants and the lower molecular weight for
w
DDS. Thus, it seems useful to link the synthesis conditions to M of the polymer. The
w
content of D centers in PLA (% D) should not exceed 15%.72
It was checked that essential process variable, e.g. temperature and reaction time,
catalyst concentration and mixing efficiency. During polymerization, it is challenging to
keep the mixing speed constant. A significant increase in viscosity during the process is
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responsible for this effect. So we established this variable at a constant level. The quality
of the L,L-lactide substrate used in reaction determines the molecular weight of polymer.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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3
3
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0
1
2
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5
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9
0
1
2
3
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Too high water content (>150 ppm) and/or lactic acid decrease a molecular weight of
PLA. Before each reaction, the content of water and free acids in the lactide was tested.68
The optimization carried out was to indicate a relationship of lactide conversion (ŷ ) and
1
average molecular weight (M ) (ŷ ) and content of D centers in PLA (%D) (ŷ ) on reaction
w
2
4
time (z ) catalyst concentration (z ) and temperature (z ), respectively. The second-
1
2
3
degree equation can be obtained using a rotatable compositional plane:
2
ŷ = b + Σbx + Σb xx + Σbx
i
0
i
i
ij
i
j
i i
The criteria of optimization were to maximize of conversion of lactide (ŷ ) and molecular
1
weight of polylactide (ŷ ). The percentage of the content of D centers in PLA should be
2
below 15%, ŷ . We tested the effect of the time z (1.3–4.7 h), catalyst/LD ratio z (0.08–
4
1
2
0
.42 % ) and reaction time z (143.2–176.8 °C) (Table 3).
mol
3
3
Table 3. Polymerization of L-lactide with ZnOct . Factorial 2 and rotatable designs:
2
variables at maximum and minimum levels.
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1
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2
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2
2
2
2
2
2
3
3
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3
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xi
natural variable
time (h)
(–1.682)
1.3
(-1)
2.0
(0)
3.0
(+1)
4.0
(+1.682)
4.7
x1
x2
x3
catalyst/LD ratio (%mol)
temperature (°C)
0.08
0.15
150
0.25
160
0.35
170
0.42
143.2
176.8
0
1
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1
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9
0
1
2
3
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
A rotatable 20-run design was used. This plan contains a 2-level factorial part (eight
runs with three input variables at all combinations of the +1 and –1 levels). The next part
is a star points (six runs with each of the three input variables at –1.682 and +1.682, while
the other two were at (0)). The last is replicates at the center of the design (six runs with
all three variables at 0). In all experiments, the remaining variables were constant (Table
4
). The experiments were performed in random order, and for each experiment, all four
of the response variables, y, were measured. Table 4 shows the design matrix, along
i
with the measured responses.
To shorten the discussion, without the statistical analysis details are presented in this
paper. We present here only the selected quadratic models (without insignificant
coefficients) and the most important diagrams.
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Table 4. L-lactide polymerization with ZnOct . Factorial rotatable design: experimental
2
a
b
matrix and results
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Mn
(kg/mol
)
Conversion
%)
Mw
%D
no
.
Coded variables
(
(kg/mol)
(%)
x1
x2
-1
x3
y1
ŷ1
y2
ŷ2
y3
y4
ŷ4
1
2
3
4
5
6
7
8
-1
+1
-1
-1
-1
25.6
77.4
48.3
81.6
30.4
57.2
45.6
82.4
26.4
71.0
40.5
85.2
26.1
60.0
47.0
80.9
58.1
69.6
50.5
61.9
33.9
43.4
27.7
49.3
53.7
70.3
49.9
66.5
30.5
47.2
34.3
50.9
42.9
39.0
35.5
37.4
31.4
22.2
19.9
24.3
11.0 10.6
-1
5.5
4.9
3.7
2.2
3.3
3.9
6.5
6.6
4.7
3.6
2.9
4.1
3.4
7.5
+1
+1
-1
-1
+1
-1
-1
+1
+1
+1
+1
+1
-1
-1
+1
+1
+1
-
9
0
0
0
0
0
0
19.3
90.3
34.0
65.2
50.5
51.7
23.0
89.0
37.4
66.9
57.9
54.1
13.8
49.3
59.8
73.0
73.2
45.5
16.2
44.2
65.6
65.6
74.3
41.7
12.8
25.4
28.2
44.8
49.9
30.8
3.2
4.5
3.6
0.3
3.4
3.4
2.6
0.5
1
.682
+1.68
2
10
-
11
0
0
0
0
1
.682
+1.68
2
12
-
13
0
0
12.8 12.9
10.6 9.7
1
.682
+1.68
14
2
0
0
1
5
6
0
0
0
0
55.5
55.9
56.0
56.0
67.4
65.4
65.6
65.6
34.1
36.9
4.7
5.1
4.8
4.8
1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
3
3
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1
1
7
8
9
0
0
0
0
0
0
0
0
0
0
0
0
56.8
57.3
53.7
57.7
56.0
56.0
56.0
56.0
68.7
64.6
62.5
64.7
65.6
65.6
65.6
65.6
37.5
32.5
32.4
36.5
4.8
4.7
4.9
4.4
4.8
4.8
4.8
4.8
20
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
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8
9
0
1
2
3
4
5
6
7
8
9
0
a
Constant conditions: all experiments were performed using the same raw materials;
scale: 8.64 g (0.06 mol) of L-lactide (purity >99.5%, contents of water <80 ppm and free
acids 0.3 mmol/kg; stirring rate 160 rpm, in an argon atmosphere.
b
All ŷ have been calculated from the quadratic model.
i
Conversion of lactide, ŷ (%).
1
2
ŷ = 56.0 + 19.6 x + 8.77 x – 1.12 x – 2.69 x x – 1.69 x x – 1.37 x
1
1
2
3
1
3
2
3
2
Figure 4 shows the effect of conversion of lactide, ŷ depends on the reaction time x
1
1
and catalyst concentration x , at the reaction temperature x = +1.
2
3
x
2
(cat./LD
ratio, % ol
)
Figure 4. The L-lactide conversion (ŷ ) effect on the reaction time (x ), and concentration
1
1
of catalyst, (x ); temperature (x ) = +1.
2
3
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The molecular weight of PLA (M ) ŷ , (kg/mol).
w
2
2
2
ŷ = 65.6 + 8.32 x – 9.69 x + 1.88 x x – 12.5 x – 2.69 x
2
1
3
2
3
1
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
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2
2
2
2
3
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3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 5 shows the influence of PLA molecular weight (ŷ ) depends on the reaction time
2
(
x ) and temperature (x ), at the catalyst concentration x = +1.
1
3
2
Figure 5. The polylactide molecular weight (ŷ ) in function on the reaction time (x ) and
2
1
temperature (x ); catalyst concentration (x )=+1.
3
2
Content of D centers in PLA (%D) (ŷ4).
2
ŷ = 4.79 – 0.63 x – 0.94 x + 0.73 x x +1.30 x x + 1.60 x x – 0.49 x – 1.16
4
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Figure 6 shows the influence of the content of D centre in PLA (%D) (ŷ ) on the catalyst
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concentration x and temperature x , at the reaction time x = +1.
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Figure 6. The content of D centre (ŷ ) on the concentration of catalyst (x ) and the
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temperature (x ); reaction time (x )=+1
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1
The experimental data was described very well by obtained equations. An optimal point
was calculated using the Microsoft Solver. The optimization criteria were to obtain the
maximum molar mass with lactide conversion >80% with the content of D centre <15%.
The coordinates of the optimal point are the following: z = 4.7 h, z = 0.08% , z = 176.8
1
2
mol
3
°
C. The result of the reaction under these conditions should be a polymer with M = 81.1
w
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kg/mol and conversion of 84.5% and %D=8%. The PLA with M = 82.3 kg/mol and 85.0%
w
conversion and %D=8.4% (Table 5) was obtained in a confirmatory experiment. The
obtained result, in line with the forecast, testifies to the correctness of the equations
obtained. The average molar mass of polymers was increased from 20.0 up to 70.0
kg/mol.68
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Table 5. Experimental and predicted results of polylactide synthesis with ZnOct in
2
optimal conditions
Results
calculated
experimental
conversion (%)
84.5
M (kg/mol)
%D (%)
8.0
w
81.1
82.3
85.0
8.4
Scale-up of lactide polymerization
In determining optimal conditions, a large scale laboratory process was carried out at
50 g lactide. The reaction conditions were as follow: temperature – 175 °C, catalyst
concentration – 0.08% and reaction time – 5 h. The reaction was conducted for 5 hours.
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The scale of the process has been increased six times (Fig.6). The results were similar
to those of optimization were obtained. The conversion of lactide differed approx. 1%
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(
Table 6) and M by approx. 0.4 kg/mol. High compliance was also observed on the
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content of D centers (about 0.2%).
The scale was increased 25 times. The experiment was carried out at 2 L metal reactor.
This apparatus can be used on a post-production medical PLA scale. The same
proportions were tested as on the large laboratory scale. The results that were obtained
also matched very well to those of smaller scales (lab and large laboratory). A polymer
with a high 89.2% conversion and a higher molecular weight of 86.9 kg/mol was obtained.
The content of D centers (9.6%) was similar to the one predicted by the optimization
model. It can be concluded that the received models also work well on a larger scale.
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production
scale
x 25
large lab
scale
•
1.3 kg
x 6
•
52.0 g
lab scale
•
8.64 g
Figure 7. Process scale-up diagram
Table 6. Obtained results of L-lactide polymerization at different scales
conversion
Scale
LD mass (g)
M (g/mol)
w
%D (%)
(%)
lab
8.64
52.0
1300
85.0
85.9
89.2
82.3
81.9
86.9
8.4
8.6
9.6
large lab
production
CONCLUSIONS
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An original method for synthesis biocompatible catalysts was developed. It is based on
the reaction of 2-ethylhexanoic acid with metals, e.g. zinc, calcium and magnesium. It
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was shown that ZnOct is a very good, non-toxic catalyst for PLA production. The
2
adequate mathematically models (conversion of lactide, PLA molecular weight and
contents of D centre in the polymer) for lactide polymerization catalyzed by ZnOct were
2
obtained. Polymerization conditions with ZnOct as catalyst were developed. The PLA
2
was obtained with 85% lactide conversion and an average molecular weight of 82.3
kg/mol, and D%=8.4%, without tin (II) residues. The obtained models have been shown
to work well, even when scale-up. Convergent results were obtained with a 6- and 25-fold
increase in scale. It has been shown that the developed process conditions can be
transferred to a production scale.
ABBREVIATIONS
DoE, Design of Experiments; PLA, polylactide; SnOct , tin 2-ethylhexanoate; CaOct ,
2
2
calcium 2-ethylhexanoate; MgOct , magnesium 2-ethylhexanoate; ZnOct , zinc 2-
2
2
ethylhexanoate; M , number average molecular weight; M , weight average molecular
n
w
weight.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: pawel.ruskowski@ch.pw.edu.pl
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ORCID
Agnieszka Gadomska-Gajadhur 0000-0001-7686-1745
Paweł Ruśkowski 0000-0002-4589-0727
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
Financial support obtained from Warsaw University of Technology, Faculty of Chemistry,
is gratefully acknowledged.
REFERENCES
1
Sawyer, D.J. Bioprocessing – no longer a field of dreams, Macromol. Symp. 2003, 201,
271–281.
2
Gupta, A.P.; Kumar, V. New Emerging Trends in Synthetic Biodegradable Polymers -
Polylactide a Critique, Eur. Polym. J. 2007, 43, 4053–4074.
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