Chapter 1

PLA Synthesis. From the Monomer to the Polymer

Kazunari Masutania and Yoshiharu Kimura*a
a Kyoto Institute of Technology, Japan. E-mail: ykimura@kit.ac.jp


Among the bio-based polymers developed so far, PLA polymers and their derivatives stand at the forefront of practical use and are currently manufactured. PLLA obtained from naturally occurring l-lactic acid is generally produced and utilized on an industrial scale. Two synthetic routes to PLLA have been known: one is the ROP of l-lactide and the other is the direct polycondensation of l-lactic acid. In the former method, various polymerization mechanisms have been demonstrated. Among them, bulk polymerization of l-lactide monomer in the presence of tin octoate is favoured to avoid racemization and trans-esterification (chain scrambling). This ROP method is the most convenient for controlling the molecular weight of PLLA and attaining a high molecular weight polymer (Mw>1×106). NatureWorks LLC (USA) and other current manufacturers of PLLA depend on this ROP route for their production. Many other catalysts, based on organic, cationic and metal compounds, are also effective for ROP, although their process control has not yet been fully established. The alternative direct polycondensation of l-lactic acid has been less studied compared to the ROP method. Recently, much effort has been made to establish the direct polycondensation method. A key technology for its success is the melt/solid polycondensation, by which a high molecular weight of PLLA and sb-PLA can be produced at lower cost. Stereo-complexed PLA materials and PLA copolymers consisting of different macromolecular chains can also be synthesized for higher performance and specialties. The molecular weight, terminal groups, copolymer composition and functionalities must be precisely controlled for wider application of these PLA polymers.


1.1 Introduction

It is recorded that Théophile-Jules Pelouze first synthesized poly(lactic acid) (PLA) by polycondensation of lactic acid in 1845.1 In 1932, Wallace Hume Carothers et al. developed a method to polymerize lactide into PLA. This method was later patented by Du Pont in 1954.2 Until the late 1970s, PLA and its copolymers were developed as biomedical materials based on their bioabsorbable and biocompatible nature and have been utilized in many therapeutic and pharmaceutical applications such as drug delivery systems (DDS),3,4 protein encapsulation and delivery,5,6 development of microspheres7–10 and hydrogels11etc. Recently, the biomedical application of PLA has been extended to tissue engineering12 including scaffold materials13 as well as to biocompatible materials for sutures and prostheses14 in which high- and low-molecular-weight PLAs are used, respectively. In the early 1990s, a breakthrough occurred in the production of PLA. Cargill Inc. succeeded in polymerizing high-molecular-weight poly(l-lactic acid) (PLLA) by ring-opening polymerization (ROP) of l-lactide in industrial scale and commercialized the PLLA polymer in the mid 1990s. Showing high mechanical properties in addition to a biodegradable nature, PLLA was thought to provide large opportunities to replace non-degradable oil-based polymers, such as poly(ethylene terephthalate) (PET) and polystyrene (PS). Since then, PLA has been utilized as biodegradable plastics for short-term use, such as rigid packaging containers, flexible packaging films, cold drink cups, cutlery, apparel and staple fibres, bottles, injection- and extrusion-moulds, coatings, and so on.15 All of them can be degraded under industrial compositing conditions.16 In the late 1990s, the bio-based nature of PLA was highlighted and its production as a bio-based polymer started. In this case, the newly developed polymers ought to have high-performances and long-life utilities that can compete with those of the ordinary engineering plastics. Various types of bio-based polymers are now under development, and several PLA types are also developed as promising alternatives to commercial commodities. In particular, PLLA polymers comprising high l-contents and stereo-complex PLA polymers showing high melting temperatures are now expected to be candidates for high-performance materials. The above historical view reveals the three specific features of PLA in terms of application, i.e. bio-absorbable, bio-degradable and bio-based.

Now, the synthesis of PLA polymers can be performed by direct polycondensation of lactic acid as well as by ring-opening polymerization of lactide (LA), a cyclic dimer of lactic acid. While the former method needs severe conditions to obtain a high-molecular-weight polymer (high temperature of 180–200 °C, low pressure as low as 5 mmHg and long reaction times),17–19 the latter method can afford a high-molecular-weight PLA with narrow molecular weight distribution at relatively mild reaction conditions (low temperature of 130 °C and short reaction times).20,21 Consequently, ROP of l-lactide is adopted in the ordinary industrial production of PLLA. On the other hand, since Ikada discovered the formation of stereo-complexes of PLLA and its enantiomer poly(d-lactic acid) (PDLA) in 1987, many trials have been done for its industrial production.22 Manufacturing of d-lactic acid and improvement of the stereo-complexibility of the enantiomeric segments have been the big challenges in the trials thus far.23,24 Synthesis of stereo-block polymers consisting of PLLA and PDLA macromolecular chains is a promising method for the preferential formation of stereo-complexes.25–29 This chapter deals with the whole synthetic aspects of these PLA polymers and their starting monomers.

1.2 Synthesis of Lactic Acids

1.2.1 Stereoisomers of Lactic Acid

Lactic acid (2-hydroxypropanoic acid) is the simplest 2-hydroxycarboxylic acid with a chiral carbon atom and exists in two optically active stereoisomers, namely l and d enantiomers (S and R in absolute configuration, respectively), as shown in Scheme 1.1. These l- and d-lactic acids are generally synthesized by fermentation using suitable micro-organisms. Racemic dl-lactic acid (RS configuration) consisting of the equimolar mixture of d- and l-lactic acids shows characteristics different from those of the optically active ones. dl-lactic acid is conveniently synthesized by chemical method rather than fermentation.

Scheme 1.1 Structures of l-, d- and dl-lactic acids.

1.2.2 Fermentation with Lactic Acid Bacteria

Lactic acid fermentation is one of the bacterial reactions long utilized by mankind30 along with alcoholic fermentation. The lactic acid bacteria are generally divided into several classes in terms of cell morphology, i.e. Lactobacillus, Streptococcus, Pediococcus, Aerococcus, Leuconostoc and Coryne species. They are also divided into various genera. Most of them produce l-lactic acid while some produce d- or dl-lactic acids. Table 1.1 compares which of d- or l-lactic acid is produced by different bacteria. The species belonging to the same Lactobacillus genus produce either l- or d-lactic acid preferentially. Lactobacillus helvetics and Sporolactobacillus produce dl- and d-lactic acids, respectively. In the lactic acid formation, therefore, stereoselectivity is much lower than in the amino acid formation where the absolute l-selectivity is shown. Table 1.2 shows the mono- and di-saccharides assimilated by the lactic acid bacteria.31 Each bacterium assimilates most mono-saccharides, but shows its own assimilation ability for di-saccharides. This difference in assimilation ability is important in the selection of bacteria. Since the breakdown of cellulose and starch often produces di-saccharides, the species that can assimilate these di-saccharides must be used in the fermentation. In the ordinary lactic acid fermentation, the yields of l- and d-lactic acids reach 85–90% and 70–80% based on carbon usage, respectively.24

Table 1.1 Formation of d- and l-lactic acids with different lactic acid-producing bacteria.
Strain Source Yield of l-lactic acida
Lactobacillus casei sp. Rhamnosus LC0001 IFO3425 97.5
Lactobacillus bulgarics LB0004 IAM1120 98.8
Lactobacillus delbrueckii LD0008 AHU1056 96.6
Lactobacillus delbrueckii LD0012 IAM1197 98.9
Lactobacillus delbrueckii LD0025 IFO3534 1.5
Lactobacillus delbrueckii LD0028 IFO3202 0.6
Lactobacillus helvetics LH0030 49.5
Lactococcus thermophillus LT ATCC19987 97.0
Lactococcus lactis LL0005 ATCC8000 99.0
Lactococcus lactis LL0016 AHU1101 98.6
Lactococcus lactis LL0018 IFO3443 97.1
Sporolactobacillus inulinus SI0073 ATCC15538 1.1
Sporolactobacillus inulinus SI0074 ATCC15538 1.1
a L/(D+L)×100.
Table 1.2 Saccharides assimilated by the representative lactic acid bacteria.
Strain Glucose Fructose Maltose Sucrose Cellobiose
Lactobacillus casei sp. lactis + + + + ±
Lactobacillus bulgarics + + +
Lactobacillus acidophilus + + + + +
Lactobacillus delbrueckii LD0025 + + + + +
Lactobacillus helvetics LH0030 + ± + +
Sporolactobacillu sinulinus SI0073 + +
Sporolactobacillus inulinus SI0074 + +
+: assimilative, –: non-assimilative, ±: assimilative under specific conditions.

1.2.3 Isolation and Purification of Lactic Acids

The fermenting liquor finally obtained in the above fermentation contains lactic acid together with various impurities such as un-reacted raw materials, cells and culture media-derived saccharides, amino acids, carboxylic acids, proteins and inorganic salts. Therefore, the isolation and purification steps are needed for obtaining a highly pure product needed in the polymer’s synthesis. In the usual fermentation process, the generated lactic acid is neutralized in situ with calcium oxide or ammonia. When calcium oxide is used for the neutralization, calcium lactate is precipitated out. This salt is isolated by filtration in the final step, washed with water and acidified with sulfuric acid to liberate free lactic acid with formation of calcium sulfate as solids. When ammonia is used for the neutralization, the ammonium lactate is formed and directly converted into butyl lactate by esterification with n-butanol, as shown in Scheme 1.2.32 Here, the ammonia is recovered and recycled. The following distillation and hydrolysis of butyl lactate gives an aqueous lactic acid with high efficiency. The lactic acid obtained by this method has higher purity than that obtained by the calcium salt method. The technologies for the above lactic acid fermentation and purification have well been established, and the production of both d- and l-lactic acids is conducted industrially in a plant scale of 100000 ton year−1.

Scheme 1.2 Formation of butyl lactate from ammonium lactate.

1.2.4 Chemical Synthesis of Lactic Acids

Racemic dl-lactic acid can be synthesized by fermentation using appropriate bacteria (Lactobacillus helvetics in Table 1.1), but it is more easily synthesized by following the chemical process shown in Scheme 1.3.33 Here, the dl-lactic acid is produced by hydrolysis of lactonitrile that is generally formed by the addition reaction of acetaldehyde and hydrogen cyanide. Industrially, the lactonitrile is obtained as a by-product of acrylonitrile production (Sohio process).34 The lactic acid thus prepared is purified by distillation of its ester as described above.

Scheme 1.3 Chemical synthesis of lactic acid via lactonitrile.

1.3 Synthesis of Lactide Monomers

1.3.1 Stereoisomers of Lactides

Scheme 1.4 shows three lactides consisting of different stereoisomeric lactic acid units. l- and d-lactides consist of two l- and d-lactic acids, respectively, while meso-lactide consists of both d- and l-lactic acids. Racemic lactide (rac-lactide) is an equimolar mixture of d- and l-lactides. The melting points (Tm) of these lactides are compared in Table 1.3. Note that the Tm is higher in rac-lactide and is lower in meso-lactide.

Scheme 1.4 Structures of various lactides.
Table 1.3 Thermal properties of lactides.
Melting point (°C)
l-lactide 95–98
d-lactide 95–98
meso-lactide 53–54
rac-lactide 122–126

1.3.2 Synthesis and Purification of Lactides

Each of the aforementioned lactides is usually synthesized by depolymerization of the corresponding oligo(lactic acid) (OLLA) obtained by polycondensation of relevant lactic acid, as shown in Scheme 1.5.32 Because of the ring-chain equilibrium between lactide and OLLA, unzipping depolymerization generates lactide through the back-biting mechanism involving the -OH terminals of OLLA as the active site as shown in Scheme 1.6.35 This reaction is well catalyzed by metal compounds involving Sn, Zn, Al and Sb ions, etc. The crude lactide can be purified by melt crystallization or ordinary recrystallization from solution.

Scheme 1.5 Synthetic route to lactide from lactic acid via oilgolactide.
Scheme 1.6 Expected formation mechanism of lactide (back-biting mechanism).

1.4 Polymerization of Lactide Monomers

1.4.1 Structural Diversities of the Polylactides

As shown in Scheme 1.7, there are two major synthetic routes to PLA polymers: direct polycondensation of lactic acid and ring-opening polymerization (ROP) of lactide. Industrial production of PLA mostly depends on the latter route. The polymerization of optically pure l- and d-lactides gives isotactic homopolymers of PLLA and PDLA, respectively. Both PLLA and PDLA are crystalline, showing a Tm around 180 °C. Their crystallinity and Tm usually decrease with decreasing optical purity (OP) of the lactate units.36 Optically inactive poly(dl-lactide) (PDLLA), prepared from rac- and meso-lactides, is an amorphous polymer, having an atactic sequence of d and l units. However, crystalline polymers can be obtained when the sequence of both d and l units are stereo-regularly controlled.37 The most interesting issue comes from the fact that mixing of isotactic PLLA and PDLA in 1:1 ratio affords stereo-complex crystals (sc-PLA) whose Tm is 50 °C higher than that of PLLA or PDLA.22,38–45 This sc-PLA is formed by co-crystallization of the helical macromolecular chains having opposite senses. Stereo-block copolymers (sb-PLA) consisting of isotactic PLLA and PDLA sequences are also synthesized by stereo-regular polymerization techniques involving block copolymerization.45 These structural diversities of PLA polymers provide a broad range of physicochemical properties for PLA materials when processed.

Scheme 1.7 A variety of microstructures of lactides and PLAs.

1.4.2 Thermodynamics for the Polymerization of d- and l-Lactides

The heat capacities and enthalpies of combustion were measured to analyze the thermodynamics of polymerization of d- and l-lactides into their polymers.46,47 The enthalpies and entropies of the lactide polymerization determined from these data are as follows: ΔHp=−27.0 kJ mol−1 and ΔSp=−13.0 J mol−1 K−1 at 400 K, indicating an exothermic reaction. The kinetics of ROP of lactide have also been studied with various catalysts, showing that the polymerization rate is in first-order of each of the monomer and catalyst concentrations.

Witzke proposed a reversible kinetic model for the melt polymerization of l-lactide in the presence of tin(II) octoate as the catalyst and determined the following parameters:48 Ea=70.9±1.5 kJ mol−1, ΔHp=−23.3±1.5 kJ mol−1 and ΔSp=−22.0±3.2 J mol−1 K−1, and ceiling temperature (Tc)=786±87 °C. Model equations for monomer concentration and conversion as a function of time were derived as follows: Mt=Meq+(M0Meq)exp(−KpIt) (1) image file: BK9781849738798-00001-t2.tif (2) Kp=86.0exp{(−Ea/R)(1/T−0.00223)} (3) where Meq=(ΔHp/RT−ΔS/R) Mt=monomer concentration at time Meq=equilibrium monomer concentration M0=initial monomer concentration Kp=propagation rate constant in (1/cat.mole %-hr) I=catalyst concentration in (mole %) t=time in hours Xt=monomer to polymer conversion at time t Ea=activation energy R=gas constant T=polymerization temperature in Kelvin ΔH=enthalpy of polymerization ΔS=entropy of polymerization

Three reaction mechanisms have been proposed thus far for ROP of lactide: anionic, cationic and coordination mechanisms.15,16 In the anionic polymerization, undesirable reactions such as racemization, back-biting reaction and other side reactions are often caused by the highly active anionic reactants that hinder the chain propagation. In the cationic polymerization, undesirable side reactions and racemization likely occur because of the nucleophilic attacks on the activated monomers and the propagating species. The decreases in molecular weight and optical purity lower the crystallinity and mechanical properties of the obtained polymers. On the contrary, coordination polymerization with metal catalysts (mostly alkoxides) can give a large molecular weight with the high optical purity maintained. Therefore, a variety of catalysts have been studied. The following sections deal with these polymerization aspects in detail.

1.4.3 Metal Catalysts

Metal complexes of Al, Mg, Zn, Ca, Sn, Fe, Y, Sm, Lu, Ti and Zr have been widely used as the catalysts in the ROP of various lactone monomers involving lactides. The standard catalyst system utilized for lactide polymerization is tin(II) octoate (stannous bis(2-ethylhexanoate): Sn(Oct)2),49–52 to which lauryl alcohol (1-dodecanol) is usually added as a real initiator. This catalyst system has many advantages over the other systems in that it is highly soluble in organic solvents and molten lactide in bulk state and very stable on storage. It also shows excellent catalytic activity to give high molecular weight of PLLA.16 The most important characteristic is that this catalyst is biologically safe and approved by the FDA (the US Food and Drug Administration) for use in medical and food applications, although the approval is dependent on empirical safety data.53 With these characters, Sn(Oct)2 has been used as the catalyst in the industrial production of PLAs.

The mechanism of this tin-catalyzed polymerization of lactide has been disputed for a long time, i.e. discussing whether the polymerization is induced by “insertion-coordination mechanism” or “monomer activation mechanism”.54,55 Duda and Penzek proposed a comprehensive polymerization scheme based on the insertion-coordination mechanism.51 In the ordinary lactide polymerization catalyzed by Sn(Oct)2, a hydroxyl compound (alcohol) is added as the real initiator. The alcohol initiator first reacts with Sn(Oct)2 to generate a tin alkoxide bond by ligand exchange. In the next stage, one of the exocyclic carbonyl oxygen atoms of the lactide temporarily coordinates with the tin atom of the catalyst having the alkoxide form. This coordination enhances the nucleophilicity of the alkoxide part of the initiator as well as the electrophilicity of the lactide carbonyl group. In the next step the acyl-oxygen bond (between the carbonyl group and the endocyclic oxygen) of the lactide is broken, making the lactide chain opened to insert into the tin-oxygen bond (alkoxide) of the catalyst. The following propagation is induced by identical mechanism and continues as additional lactide molecules are inserted into the tin-oxygen bond (Scheme 1.8).56–59

Scheme 1.8 ROP of lactide with tin octoate by coordination-insertion mechanism.

This mechanism was strongly supported by the MALDI-TOF mass spectrum showing molecular peaks that correspond to the oligomeric PLLA chains connecting with the tin residue, which are propagating species formed with the Sn(Oct)2/lauryl alcohol system. Since the polymerization is pseudo-living, the molecular weight can be relatively well controlled. However, in the last stage of propagation where the monomer concentration becomes significantly lower, the reverse depolymeriztion by back-biting mechanism as well as intermolecular trans-esterification that is referred to chain transfer or polymer interchange reaction becomes evident to broaden the molecular weight distribution.60 Despite the presence of this mechanism, the degrees of racemization and chain scrambling are much lower than those with anionic or cationic catalysis.

Figure 1.1 shows a typical time-conversion curve in the melt-polymerization of l-lactide at 190 °C in the presence of Sn(Oct)2 (1.78×10−5 mol%) and lauryl alcohol (0.205 mol%). It is shown that at the beginning of the polymerization process, the monomer consumption is fast to reach 94.7% within 30 min. The plateau observed thereafter indicates that the polymerization has reached the ring-chain equilibrium state where the amount of remaining monomer corresponds to the equilibrium monomer concentration. Here, the theoretical Mn estimated from the monomer/initiator ratio was 70 kDa, being identical to the Mn value of the final product. The weight average molecular weights (Mw) of the PLLA polymers thus obtained reach 500–700 kDa at maximum, if the monomer/initiator ratio is properly adjusted.

Fig. 1.1 A typical time-conversion curve in the tin-catalyzed ROP of l-lactide.

The catalyst and monomer remaining in the PLA polymers are problematic, because they are likely to cause the degradation of PLA polymers.61 In particular, the catalyst promotes chain breakage of PLA polymers during the melt processing. Since the catalyst is not easily removed, it is generally deactivated by adding a deactivator such as sodium phosphonate in the final step of the ROP. As noted by Figure 1.1, the remaining monomer present in the final polymer reaches ca. 5 wt% when melt polymerization of lactide is conducted with Sn(Oct)2/lauryl alcohol system at 180–200 °C. This lactide monomer is quickly hydrolyzed and stimulates the hydrolytic degradation of PLA polymers. It also plasticizes the PLA materials to lower the Tg and Tm values.62 Therefore, the remaining monomer is removed by vacuum evaporation to a concentration lower than 0.1 wt%. The remaining monomer concentration can be also decreased by performing the ROP in solid-state. When the polymer melt is crystallized during polymerization, the monomer and catalyst are concentrated in amorphous domains to make the ring-chain equilibrium decline to the polymer side. Figure 1.2 shows typical results of the ROP of l-lactide conducted at 120, 140 and 160 °C.57 The concentration of the remaining monomer decreases to zero at 120 and 140 °C where the polymerization systems turn to solid state, whereas at 160 °C the monomer consumption reaches a plateau with the melt-state retained. The same technique is utilized to increase the molecular weight of PLA in the solid-state polycondensation of lactic acid (vide infra).

Fig. 1.2 Changes in monomer consumption and polymer crystallinity during lactide polymerization at (○) 120 °C (crystallization), (□) 140 °C (crystallization) and (▲) 160 °C (melt state).

Aluminium alkoxides have also been utilized as efficient catalysts for the lactide polymerization. The most popular one is aluminium isopropoxide (Al(OiPr)3).63 Duda verified that Al(OiPr)3 exists in two types of aggregates: a trimer (A3) and a tetramer (A4) as shown in Scheme 1.9.64 The A3, consisting of penta-coordinate aluminium ion, can initiate the lactide polymerization whilst A4, having hexa-coordinate aluminium ion, is ineffective for the ROP. Since A4 is equilibrated with A3, the ROP of lactide is slowly initiated in the presence of A4. All of the alkoxyl ligands in the aluminium alkoxides are involved in the initiation because interligand exchange of the propagating metal alkoxides is fast.

Scheme 1.9 Aggregation structures of a trimer (A3) and a tetramer (A4) of aluminium triisopropoxide (R=CH(CH3)2).

Other metal alkoxides are also effective for the ROP of lactides.65 Depending on the Lewis acidity of the metal ion (or the availability of open coordination sites), the metal alkoxides can activate the monomer by binding to the carbonyl.49,66–70 In case the trans-esterification of the propagating metal alkoxide is slow, the metal alkoxide functions as an initiator, whereas it works as a catalyst when the metal alkoxide reacts with alcohols to regenerate a new metal alkoxide. It is known that the active alkoxide end-groups quickly interchange with the other polymer chains and affect the molecular weight distribution of the final polymer. Furthermore, the metal alkoxides, including those formed from Sn(Oct)2 and alcoholic initiators, remain attached to the propagating species, making it difficult to be removed from the final polymer. They ought to affect the thermal properties of the final polymers, in particular causing deterioration of their melt processability at high temperature even though they have been deactivated. With increasing applications of PLA polymers in packaging, biomedical and microelectronic fields, development of more biocompatible metal catalysts65,71 or metal-free organic catalysts (below) is needed.

1.4.4 Cationic Catalysts

The ROP of lactide can be induced by the catalysis of strong organic acids.72 In the ordinary cationic ROP, strong organic acids, such as super acids, are utilized as the catalysts as shown in Scheme 1.10. In the initiation step, the monomer activated by the protonation is ring-opened by the carbonyl attack of an alcohol initiator to form the lactyl alcohol with recovery of acidic proton. Successive attack of this lactyl alcohol on the protonated monomers propagates the polymer chain. Namely, the terminal hydroxyl group acts as the propagating species reacting with the protonated monomer, which corresponds to the monomer activation mechanism. Since the acid catalyst is free from the propagating polymer, it is readily removed, and fewer than one catalyst per monomer chain is needed.73 This feature is an advantage of the cationic catalysts over the metal alkoxides, which ought to remain attached to the propagating chains as described above. In the acid-catalyzed ROP, however, the propagation is likely contaminated by chain termination or transfer reactions that may be related to the reactivity of the protonated monomer.74

Scheme 1.10 Mechanism of the cationic ROP of lactide (monomer activation mechanism).

The acid-catalyzed polymerization of lactide (LA) with tri-fluoro-methanesulfonic acid (HOTf) can be highly controlled in the presence of an alcohol initiator.58 The low molecular weights, slow rates and high catalyst loadings associated with organic acids may be compensated by the operational simplicity of this process. It is also confirmed that the polymerization of l-lactide is highly stereospecific.58,74 On the other hand, cationic ROP of lactide with strong methylating agents, such as methyl tri-fluoro-methanesulfonate (MeOTf)72 has not yet been optimized in terms of polymerization mechanism.

1.4.5 Organic Catalysts

As mentioned above, much effort has been put in to developing more biocompatible metal-free organic catalysts for the use of PLA materials in biomedical and microelectronic applications. Scheme 1.11 summarizes the organic catalysts recently developed for the ROP of various lactone monomers.

Scheme 1.11 Representative organic catalysts and initiators.

The first ROP of lactide with organic bases was reported with 4-(dimethylamino) (DMAP) and 4-pyrrolidino-pyridines (PPY) as the catalysts.75–80 DMAP produces PLAs having a degree of polymerization (DP) of 100 with narrow dispersity (PDI<1.13) in solution, while PPY was effective only for the ROP of lactide in the melt state. DMAP is believed to activate an alcoholic initiator which may successively react with lactide monomers.81

N-heterocyclic carbenes (NHCs), having higher basic character than DMAP, are also effective for the ROP of lactide.82–84 For example, an aryl-substituted carbene IMes is very active for lactide polymerization but less active for the polymerization of ε-caprolactone (CL). The alternative more basic carbenes Me2IMe and Me2IPr are more effective than IMes, polymerizing both lactide and CL.85 The polymerization of lactide is extremely rapid with IMes in which a feature of living polymerization is retained. In the absence of alcohol initiators this carbene forms a zwitterionic active species to generate a cyclic polylactide.86

Guanidine and amidine derivatives, such as N-methyl-1,5,7-tri-azabicyclododecene (MTBD) and di-azabicycloundecene (DBU), show similar catalytic activities for the polymerization of lactide,87,88 producing polymers with a DP reaching 500 and narrow dispersity (PDI<1.1). The polymerization finishes within an hour although trans-esterification involving the chain scrambling occurs at a considerable rate. An alcohol-activated mechanism is proposed. These catalysts are not effective for the ROP of butyrolactone, valerolactone or CL at up to 20 mol% catalyst loading.

Hong Li et al. demonstrated that simple 1,1,2,2,3,3-hexa-alkylguanidinium acetate (HAG·OAc) and creatinine lactate exhibit excellent catalytic activity in the ROP of lactides and produce PLA polymers with a DP of 140 and narrow dispersity (PDI<1.1).89,90 Living polymerization driven by a carboxylate-activation mechanism is supported by the kinetic studies on the HAG·OAc-initiated ROP. The proposed mechanisms for the ROP initiated with HAG·OAc and creatinine are shown in Schemes 1.12 and 1.13, respectively. The use of bio-originated creatinine may guarantee the bio-safety required in biomedical application.

Scheme 1.12 Proposed mechanism for the ROP of lactides initiated with HAG·OAc.
Scheme 1.13 Proposed mechanism for the ROP of lactides initiated with creatinine.

A combination of a thiourea (TU) and a tertiary amine (TA) gives an active catalyst for the ROP of lactide.91 The catalytic activity is modulated by changing the thiourea. In a typical run, PLA having a narrow PDI (<1.08) is produced with TU with living polymerization features because Mn is critically correlated to the monomer-to-initiator ratio. The thioureas are thought to activate the monomer carbonyls through the hydrogen bonding. Similar combined catalysts TU/MTBD and TU/DBU are also highly effective for the ROP of various lactone monomers including lactide.92

A bicyclic guanidine, 1,5,7-tri-azabicyclododecene (TBD), shows much higher activity than DBU and MTBD in the ROP of cyclic monomers.93 The ROP of lactide finishes within 1 min. with 0.1 mol% of TBD88 whereas ca. 30 min. is required in the presence of 0.5 mol% MTBD. TBD shows a living polymerization nature, but induces trans-esterification at high conversion, resulting in the broadening of dispersity.

Alkyl and alcohol adducts of saturated N-heterocyclic carbenes (NHCs) are also used in the ROP of lactide. In these systems, NHC catalysts are generated in situ at elevated temperatures (65–144 °C) to polymerize lactide in the presence of an alcohol initiator.94–96 For example, alcohol adducts of SIMes act as single-component catalyst/initiators for the ROP of lactide. As shown in Scheme 1.14, they reversibly liberate the alcohol initiator with the carbene catalyst at room temperature to induce ROP of lactide. PLA having narrow polydispersity is obtained within minutes in high yields.

Scheme 1.14 Polymerization of lactide by reversible activation and deactivation of SIMes.

On the other hand, alcohol adducts of triazol-5-ylidene are stable at room temperature and reversibly dissociate into the alcohol and carbine only at 90 °C.97–100 The triazolylidene catalysts are inactive at room temperature even in the presence of alcohols, but at 90 °C they polymerize lactide into PLA of narrow dispersity (Scheme 1.15). The reversible formation of the active and dormant carbene species is the key factor to control the polymerization.

Scheme 1.15 Polymerization of lactide by reversible activation of triazolylidene carbenes.

1.4.6 Stereo-controlled Polymerization

Stereochemistry is one of the most important factors that determine the physical and chemical properties of polymeric materials. Spassky et al. developed the first catalyst system for the stereoselective polymerization of dl-lactide into isotactic PLA.101 They used Al complexes containing achiral salen ligands to synthesize a multi-block PLLA and PDLA stereo-copolymer (Scheme 1.16). Spassky also reported a one-step synthesis of gradient PLA from dl-lactide by using homochiral catalysts.102 Since then, many other single-site catalysts supported by various kinds of multi-valent ligands were made and used for well-controlled or stereoselective polymerizations of lactide to demonstrate the synthetic possibilities from dl-lactide to stereo-regular PLA materials.101–114 In general, the single-site catalysts used thus far function with two different mechanisms: (1) chain-end control mechanism103,110 and (2) site control mechanism.113 In the chain-end control mechanism, the configuration of the next inserted monomer is selected by the stereo-genic centre in the last repeating unit in the propagating chain. In the site control mechanism, the configuration of the inserted monomer is determined by the configuration of the ligands surrounding the catalyst site. If the dl-lactide polymerization follows either the chain-end control mechanism or the site control mechanism, only isotactic or heterotactic (having iso-syndio repeating units) PLA can be obtained.

Scheme 1.16 Synthesis of multi-sb-PLA by stereoselective ROP of racemic dl-lactides.

Table 1.4 summarizes the representative aluminium catalysts reported thus far. Although many other metal catalysts have also been reported, they are not included here because of their lower catalytic activities.65

Table 1.4 Synthesis of multi-sb-PLA by ROP of rac-lactide with various aluminium catalysts.
Structure of Initiator/Catalyst Solvent Temp. (°C) Time (h) Mn [GPC] Mw/Mn [GPC] Tm(°C) Pmeso Block length Ref.
Type R1 R2 R3 X
1 H H OCH3 A Toluene 70 281 12,700 187 1
H H OCH3 (CH2)2 CH2CI2 70 95 17,300 1.2 164 7.6 2
H H OiPr (CH2)2 (Solution) 1.05 191 3
H H OiPr (CH2)2 Toluene 70 40 22,600 1.09 179 11 4
tBu tBu OiPr B Toluene 70 288 7,700 1.06 183.5 0.93 5
tBu tBu OiPr (Bulk) 130 48 24,900 1.37 0.88 5
H ph Et (CH2)3 (Solution) 70 1.3 20,000 1.1 170 0.81 6
tBu tBu Et (CH2)3 (Solution) 70 14 22,400 1.06 192 0.91 8
tBu tBu OBn CH2C(CH3)2CH2 (Bulk) 130 0.5 14,300 1.05 169 0.91 8
tBu tBu Et CH2C(CH3)2CH2 Toluene 70 17.25 14,900 1.05 193 0.90 9
tBu tBu OiPr CH2C(CH3)2CH2 Toluene 70 8.95 22,300 1.04 196 0.90 20 10
H H OiPr A THF 80 25 12,300 1.11 210 11
2 CH3 H CH3 (CH2)2 Toluene 70 21 21,180 1.08 0.79 7
3 ph CH2C(CH3)2CH2 Toluene 70 5.6 36,800 1.04 0.78 12

1.4.7 Stereo-block Copolymerization

Mixing of enantiomeric PLLA and PDLA generates stereo-complex (sc) crystals that exhibit high Tm about 230–240 °C, being 50 °C higher than those of the single PLLA or PDLA polymers.22,38–45 The resultant stereo-complex-type poly(lactic acid)s (sc-PLA) ought to be more thermally stable, possessing wider application. However, the melt-blending of PLLA and PDLA having high molecular weight is likely accompanied by their homo-chiral (hc) crystallization together with the sc crystallization, resulting in a mixed crystalline state and a deteriorated performance of the processed materials. Therefore, various trials have been made for improving the miscibility of PLLA and PDLA.115,116 Among them, making block copolymers of PLLA and PDLA, i.e. stereo-block-type poly(lactic acid)s (sb-PLA), has been found to be highly effective for generating the stereo-complex, because the neighbouring d- and l-stereo-sequences can readily interact with each other to fall into molecular mixing state.27–29

In 1990, Yui et al. first prepared a diblock copolymer of PLLA-b-PDLA by step-wise ROP of l- and d-lactides (Scheme 1.17) to demonstrate its easy sc formation with little hc crystallization.115 However, the highest molecular weight (Mn) obtained was as low as 20.1 kDa, with which the sc crystallization is known to predominantly occur even by mixing PLLA and PDLA homopolymers.

Scheme 1.17 Two-step ROP to synthesize diblock sb-PLAs.

Later, the synthesis of sb-PLA having defined block length and sequence was performed by the stepwise ROP method,27,28 consisting of three steps: 1) polymerization of either l- or d-lactide to obtain PLLA or PDLA having molecular weight of 7–100 kDa (preferably lower than 50 kDa), 2) purification of the obtained polymer to remove the residual lactide and 3) polymerization of the enantiomeric lactide in the presence of the purified polymer. The purification step is important to avoid racemization of the second block. Table 1.5 shows some results together with the characteristics of the sb-PLA polymers produced. The preferable PLLA/PDLA ratio is in the range from 85/15 to 15/80 where the resultant diblock sb-PLAs show almost exclusive sc crystallization without the hc crystallization occurring. The shorter and longer blocks of these copolymers must be synthesized in steps 1 and 3, respectively, for the pre-polymer first prepared in step 1 can be well solvated by the larger amount of lactide monomer with opposite chirality and promote the chain elongation from its terminal in step 3. When the longer block is first made, the chain extension in the second ROP becomes imperfect to retard the block copolymerization. When the PLLA/PDLA ratio is higher than 90/10 and lower than 10/90, the sc crystallinity of the resultant sb-PLA becomes lower than 80%. The sb-PLAs prepared by this method are useful not only because preferential sc crystallization is possible even at non-equivalent PLLA/PDLA ratios, but also because the more expensive d-lactide monomer is required in a smaller amount for obtaining the sc materials.

Table 1.5 Diblock sb-PLA obtained by the controlled two-step ROP.
Sample No. Feed ratio Mw(GPC) ΔHms Xs Tm
Da (J g−1) (%) (°C)
PLA 20/80 L 20/D 80 141,000 44.2 100 210.0
PLA 80/20 D 20/L 80 143,000 36.2 100 208.5
PLA 35/65 L 35/D 65 166,000 40.4 100 212.4
PLA 65/35 D 35/L 65 159,000 38.5 100 208.5
ΔHms: Heat of melting of stereo-complex crystal. Xs: Percentage of stereo-complex crystal against homo-chiral crystal in sb-PLA.

1.4.8 Copolymerization

Various lactate copolymers have been developed thus far to tune the properties of PLLA and cope with different applications.117 Two synthetic approaches are available for the copolymerization: (1) ring-opening copolymerization of l-lactide with other monomers such as ε-caprolactone, glycolide and depsipeptides; and (2) use of new cyclic monomers consisting of lactate and other monomer units. In the former approach, random copolymers are usually prepared and the unit compositions of the comonomers are limited to 10 mol% to retain the polymer crystallinity. For example, copolymerization of l-lactide and ε-caprolactone (CL) gives a copolymer showing Tm around 150 °C at a unit composition of 90/10.118 Various copolymers of glycolide have been synthesized by this technique for making bio-absorbable sutures, such as polyglactin (glycolide/l-lactide)119 and polyglyconate (glycolide/trimethylene carbonate).120Scheme 1.18 summarizes the monomers copolymerized with l-lactide for synthesizing functional PLA polymers.

Scheme 1.18 Monomers copolymerized with l-lactide for synthesizing functional PLA polymers.

In the second approach, new cyclic diester monomers, 3S-(benzyloxymethyl)-6S-methyl-1,4-dioxane-2,5-dione (BMD)121 consisting of both l-lactate and α-O-benzyl-glycerate units and 3S-phenyl-6S-methyl-1,4-dioxane-2,5-dione (PMD)122 consisting of mandelate and lactate units, have been synthesized by base-catalyzed cyclization of the coupling products of the corresponding hydroxyl-acids with 2-bromo-propionyl chloride. These monomers can be homo-polymerized and copolymerized with other cyclic monomers to obtain polymers having improved properties. The glyceric acid-containing polymers prepared from BMD can be utilized as functional biomedical materials (Scheme 1.19).123

Scheme 1.19 Synthesis of glyceric acid containing PLA by ROP of BMD and subsequent hydrogenolysis for deprotection.

Many block copolymers consisting of PLLA or PDLA have also been prepared.124 Variation of the chain length of the PLLA or PDLA and modification of the copolymerized chains allow us to tune the mechanical properties, degradation rates and crystallinity. For example, the ordinary ROP of l- or d-lactide initiated with poly(ethylene glycol) (PEG) and poly(ethylene glycol) monomethyl ether (MePEG) can give amphiphilic PLA-PEG block copolymers with different types.124Scheme 1.20 compares a set of the related copolymers of ABA, BAB and AB types.125 The BAB triblock copolymers can be obtained by the coupling of the AB diblock copolymers with hexamethylene diisocyanate.126 These amphiphilic copolymers readily form core-shell type micelles in water by placing the hydrophobic PLA and hydrophilic PEG segments in the core and shell, respectively, as shown in Scheme 1.20. The average hydrodynamic diameters of the micelles measured by dynamic light scattering (DLS) are in the range of 20–30 nm for 1 wt% solutions of the respective copolymers. These micelles can be utilized in drug delivery and cell-growth as matrices.124–126

Scheme 1.20 Polymer structures of PLLA-PEG block copolymers and schematics of their micelles formed in aqueous media.

When aliphatic polyester pre-polymers are used as the macro-initiators of the lactide polymerization, various block copolymers consisting of soft (polyester) and hard (PLA) blocks can be obtained.127Scheme 1.21 shows a typical synthetic route to the block copolymers (PLA-PCL) of poly(ε-caprolactone) (PCL) and polylactide (PLA) in which Sn(Oct)2 is used as the catalyst for the ROP of CL and lactides.128 The di- and triblock copolymers can be obtained by using the mono-ol- and diol-type PCL pre-polymers as the macro-initiators in the lactide polymerization. Here, the PCL pre-polymers can be prepared by using a mono-ol (e.g. 1-dodecanol and benzyl alcohol) and a diol (e.g. 1,6-hexanediol) as the initiators of the CL polymerization, respectively. The resultant di- and triblock copolymers show two endothermic peaks at 40–55 °C and 140–170 °C on their DSC curves because of the separate crystallization of PLA and PCL having poor compatibility.129,130 Furthermore, many studies have been done on the stereo-complexation between various sets of block copolymers comprising PLLA and PDLA, particularly for the AB- and ABA-type block copolymers where A is PLLA or PDLA and B is its enantiomer.130 Mixing of the above enatiomeric copolymers PLLA-PCL and PDLA-PCL affords sc crystals by which Tm becomes higher than 200 °C.

Scheme 1.21 Synthesis of a triblock copolymer PLLA-PCL-PLLA (as an example utilizing 1,6-hexandiol as the initiator for the ROP of CL).

1.5 Polycondensation of Lactic Acids

No one had believed that direct polycondensation of l-lactic acid can give a high molecular weight of PLLA, until 1995 when Mitsui Chemical Co. first succeeded in synthesizing such a PLLA by using a special solution polycondensation technique.17 With this epoch-making success, many researchers including the present authors made efforts to establish the direct polycondensation of l-lactic acid. As shown in Scheme 1.22, two equilibria exist in the dehydrative polycondensation of l-lactic acid: one is hydration/dehydration equilibrium of carboxyl and hydroxyl terminals, and the other is ring/chain equilibrium between l-lactide and PLLA.

Scheme 1.22 Equilibrium reactions of PLLA and its monomers, l-lactic acid and l-lactide.

The former equilibrium constant K, defined by the ordinary equilibrium equation (eqn (5)), can be determined by measuring the amounts of hydroxyl and carboxyl groups formed by the acid hydrolysis of PLLA as well as the remaining water (eqn (4)).131 Assuming that the relation [COOH]=[OH] is always maintained, the average degree of polymerization (DP) can be correlated with K when x is the molar ratio of water relative to ester, i.e. x=[H2O]/[–COO–]. –COOH+HO–↔–COO–+H2O (4) K=[COOH][OH]/[–COO–][H2O] (5) DP-1=[–COO–]/[COOH]=(1/xK)1/2 (6)

The K values were roughly determined to be 1.5 at room temperature and 0.5 at 50 °C, being comparable with those for the ordinary ester formation reactions. Substituting the K value of eqn (6) by these values, the change in Mn of PLLA can be deduced as a function of x. Figure 1.3 shows a typical plot for the Mn change. Since this change is based on the equilibrium constant at room temperature, the real Mn value would be slightly different at higher equilibrium temperatures. It is, however, evident that the water content should be less than 1 ppm to make the Mn value of PLLA exceed 50 kDa that corresponds to 100 kDa in weight-average molecular weight (Mw) assuming Mw/Mn=2.0 in the ordinary polycondensation.

Fig. 1.3 Relation of the molecular weight (Mn) and water content of PLLA in the polycondensation.

The other ring-chain equilibrium constant is provided by the equilibrium monomer (l-lactide) concentration [M]e that is affected by the back-biting reaction of the hydroxyl terminal. As mentioned in the preceding section, the [M]e are lower than 1.0 wt% below 120 °C and higher than 5 wt% above 180 °C in the ROP of l-lactide. High evacuation, needed to remove condensed water, is likely to result in the removal of l-lactide from the system and reduce the polymer yield. Therefore, reaction conditions must be controlled to obtain high molecular weight of PLLA by direct polycondensation.

The above thermodynamic analysis of the polycondensation reveals that PLLAs having high molecular weights may be produced when the condensed water is efficiently removed to a level of 1 ppm from the polymerization system without evaporation of the l-lactide monomer present in equilibrium. The ordinary reaction conditions that may allow the effective removal of the water may involve: (1) a temperature range of 180–200 °C; (2) a low pressure below 5 torr; and (3) a long reaction time in the presence of an appropriate catalyst and, in some cases, azeotropic solvent for removing water efficiently.57

1.5.1 Solution Polycondensation

In 1995, as mentioned above, Ajioka et al. first succeeded in synthesizing PLLA having Mw higher than 100 kDa by using diphenyl ether as an azeotropic solvent.17 In this polycondensation system the high boiling solvent was refluxed at reduced pressure to azeotropically distil the condensed water and to make it adsorb on molecular sieves. This method is especially effective for the co-polycondensation of l-lactic acid with other monomers (hydroxyl-acids and diol/dicarboxylic acid combinations).

1.5.2 Melt/Solid Polycondensation

Following the success of the solution polycondensation, bulk polycondensation of l-lactic acid was studied to eliminate the use of solvent. The simplest melt-polycondensation can be obtained by continuous dehydration of oligo(l-lactic acid) with various ionic metal catalysts.18,132 This process, however, is likely accompanied by unfavourable discoloration of the product as well as by the depolymerization to l-lactide. Kimura et al. found out that use of a bi-component catalyst system comprising tin dichloride hydrate and p-toluenesulfonic acid (TSA) is effective not only for increasing the molecular weight but also for preventing the discoloration of PLLA in the melt polycondensation of l-lactic acid.133 As a result, a high molecular weight of PLLA (Mw≥100 000 Da) can be obtained within a short reaction time. Bi-component catalyst systems comprising Sn(II)-Ge(IV) and Sn(II)-Si(IV) are also demonstrated to be effective as the catalysts for producing high-molecular-weight PLLA.134

The alternative melt/solid polycondensation of l-lactic acid was also established by utilizing the bi-component catalyst comprising Sn(II) and TSA.133,135 First, l-lactic acid is thermally dehydrated to prepare an oligomeric PLLA having a degree of polymerization of ca. 8. It is then mixed with the bi-component catalyst and subjected to melt-polycondensation at 180 °C for 5 h to obtain a melt-polycondensate having an average molecular weight of 13 000 Da. This melt-polycondensate is finally heat-treated at 105 °C for crystallization and subjected to solid-state polycondensation (SSP) for chain extension at a temperature of 140 or 150 °C. The molecular weight of the SSP products increases above 500 kDa in a relatively short reaction time. In the SSP, the polymer tails and catalysts are allowed to concentrate in the amorphous domain with the polymer crystallization, inducing the chain extension efficiently. Figure 1.4 shows the typical changes in Mw as a function of crystallinity of PLLA at two different temperatures. It is clearly shown that the time-dependent increase in crystallinity is well correlated with the increase in molecular weight. Since the SSP can be conducted on a large scale in a continuous way, it will afford a facile industrial route to the synthesis of PLLA.

Fig. 1.4 Changes in Mw of PLLA as a function of polymer crystallinity in the solid-state polycondensation at (a) 140 °C and (b) 150 °C.

The direct polycondensation technique can be applied to the syntheses of various copolymers that should have different properties and degradability. For example, copolymers of l-lactic acid and phenyl-substituted α-hydroxy acids, such as l- and d-mandelic acids (l-, d-MA) and phenyl-lactic acid (Phe-LA) have been prepared.136 Polyglactin is also obtainable by the direct co-polycondensation of glycolic acid and l-lactic acid.137,138

1.5.3 Stereo-block Polycondensation

The above direct polycondensation can be a practical route to sb-PLA, replacing the above ROP route.139 Namely, both PLLA and PDLA having medium molecular weight (20–40 kDa) are first prepared by the above melt-polycondensation method. They are mixed in melt state to easily form stereo-complex crystals. SSP of this mixture can yield sb-PLA having high molecular weight in which the stereo-block sequences are generated by the cross propagation of the PLLA and PDLA chains.

Figure 1.5 shows the increase in Mw of sb-PLA as a function of the reaction time through the whole process where the SSP is conducted at 170 °C using a 1:1 melt-blend of PLLA and PDLA having initial molecular weights of 40 kDa.140 It is shown that the Mw of the resultant sb-PLA reaches 100 kDa, although the molecular weight increase is somewhat limited. Furthermore, the polymer recovery becomes significantly lower with increasing the reaction temperature (43% at 200 °C) because of the increased depolymerization to lactides. In this equivalent stereo-mixture of PLLA and PDLA, the diad sequences formed by their hetero-chain couplings are racemic, and the crystallization of the extended chains is retarded. The polymer tails excluded out of the sc domain are likely to lose their mobility due to its strong bond to crystal lattices, having a retarded reactivity in the amorphous domain. Consequently, a high reaction temperature is needed for the polycondensation of the chain ends to trigger trans-esterification and depolymerization by which the randomized sequences are formed together with sublimation of lactides.

Fig. 1.5 Changes in Mw of sb-PLA as a function of the reaction time through the whole process involving the solid-state polycondensation conducted at 170 °C (Refs. 21,26, with permission).

The enhancement of the crystallization-induced polycondensation is easier when homopolymer domains that can induce crystallization of the extended chains are increased in ratio. For this purpose, the blending ratio of PLLA and PDLA pre-polymers is changed from 1:1.25,141 When the SSP is conducted at 140–160 °C with different PLLA-to-PDLA compositions, the molecular weight increases to higher than 100 kDa with a polymer recovery as high as 70–85%. Figure 1.6 shows the typical results for Mw changes of the final sb-PLAs as a function of PDLA ratio in the feed. It is clearly shown that the Mw becomes higher with the PLLA/PDLA ratio deviating from 1:1 or l- or d-rich compositions.

Fig. 1.6 Effect of the PDLA composition (XD) on the Mw of the final sb-PLAs. The PLLA-rich (0≤XD≤50) and PDLA-rich (50≤XD≤100) systems were separately examined with different melt-blends. The SSP was conducted at constant temperature (150 °C) for 30 h and with stepwise temperature increase (at 140 °C, 150 °C and 160 °C each for 10 h).

The obtained sb-PLAs having PLLA-rich and PDLA-rich compositions exhibit good stereo-complexity in spite of involving long homopolymer sequences,26 and the properties of the sb-PLAs can be widely tuned by changing the PLLA/PDLA composition and the length of the homopolymer sequences. This structural variety of sb-PLA will guarantee a wide range of properties and applications of PLA materials.

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