Synthesis and Production of Poly(Lactic Acid)

2

Synthesis and Production of Poly(Lactic Acid)

Chapter Outline 2.1 Introduction 2.2 Lactic Acid Production 2.2.1 Laboratory-Scale Production of Lactic Acid 2.3 Lactide and Poly(Lactic Acid) Production 2.3.1 Review of Lactide Production Technology 2.3.2 Polymerization and Copolymerization of Lactide 2.3.3 Lactide Copolymer 2.3.4 Quality Control 2.3.5 Quantification of Residual Lactide in Poly(Lactic Acid) 2.3.6 Quantification of D-Lactic Acid Content in Poly(Lactic Acid) 2.4 Catalysts for Polymerization of Poly(Lactic Acid) 2.4.1 Direct Polycondensation Route 2.4.2 Ring-Opening Polymerization Route 2.5 Conclusion References Further Reading

53 54 64 65 66 71 75 76 77 80 81 81 84 92 92 95

2.1 Introduction Poly(lactic acid) (PLA) is produced from the monomer of lactic acid (LA). PLA can be produced by two well-known processes—the direct polycondensation (DP) route and the ring-opening polymerization (ROP) route. Although DP is simpler than ROP for the production of PLA, ROP can produce a low-molecular-weight brittle form of PLA. Generally, several substances are involved in the production of PLA, and these relationships are summarized in Fig. 2.1. The LA for the process is obtained from the fermentation of sugar. LA is converted to lactide and eventually to PLA. It should be noted that there are two

Polylactic Acid. DOI: https://doi.org/10.1016/B978-0-12-814472-5.00002-9 © 2019 Elsevier Inc. All rights reserved.

53

54

POLYLACTIC ACID 1 Glucose fermentation

Polylactic acid

Lactic acid

Route 1 Direct polycondensation

Lactide

2 Polylactide

Route 2 Ring-opening polymerization

Figure 2.1 General routes of poly(lactic acid) production.

different terms, “poly(lactic acid)” and “polylactide,” for the polymer of LA. Both terms are used interchangeably; however, scientifically there is a difference because polylactide is produced through the ROP route whereas PLA is generated using the DP route. Generally speaking, the term “poly(lactic acid)” is widely used to mean the polymer that is produced from LA. (The explanation regarding the difference between PLA and polylactide is given here to help readers’ understanding.)

2.2 Lactic Acid Production LA is the basic building block for the production of PLA. It is chemically known as 2-hydroxy-propionic acid with chiral stereoisomers L (2) and D (1). Its physical properties are listed in Table 2.1. Naturally occurring LA is mostly found in the L form, while chemically synthesized LA can be a racemic D and L mixture. LA is a biologically stable substance and is highly water-soluble. Prior to the mass application of LA for the manufacture of biodegradable polymer materials, LA was widely used in industry as a solvent for metal cleaning, as a detergent, a humectant, a mordant, and for tanning leather. Its use as a humectant means that it acts as a moisturizer in cosmetic and personal hygiene products, while its use as a mordant relates to its use as an additive during color dying, in order to improve dye acceptance of fabrics in textile manufacture. LA is also added during the manufacture of lacquers and inks for better absorption on the printing surfaces. It is also used in the food industry to provide a sour taste to beverages. The addition of LA in the form of calcium lactate extends the shelf life of meat, poultry, and fish, through the ability to control pathogenic bacteria while maintaining the original flavor of the food. Many dairy products, including yogurt and cheese, taste mildly sour due to the presence of LA, which provides addition antimicrobial action in these products.

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Table 2.1 Physical Properties of Lactic Acid CAS registry no.

Chemical formula Chemical name Molecular weight Physical appearance Taste Melting point Boiling point Solubility in water (g/100 g H2O) Dissociation constant, Ka pKa pH (0.1% solution, 25
C)

50-21-5 (DL-lactic acid) 79-33-4 (L-lactic acid) 10326-41-7 (D-lactic acid) C3H6O3 2-Hydroxy-propanoic acid 90.08 Aqueous solution Mild sour 53
C .200
C Miscible 1.38 3 1024 3.86 2.9

LA and lactate are naturally present in the mammalian body when glycogen (a form of carbohydrate stored in mammalian cells) is anaerobically utilized by muscle to produce energy (i.e., during insufficient oxygen supply). Although generation of LA and lactate by muscles during anaerobic exercise can cause fatigue and soreness afterward, lactate has been found to be an important chemical for sustained exercising— lactate serves as a fuel produced by one muscle to be readily consumed by another muscle. The feeling of soreness is due to the accumulation of acidic ions caused by the glycolysis reaction. Carl Wilhelm Scheele was the first to discover LA in 1780. Since then, LA has been industrially produced using the fermentation process, with the earliest technology introduced by the French scientist Fre´my in 1881. Pure LA has two stereoisomers (also known as enantiomers), as are shown in Fig. 2.2. These two stereoisomers are synthesized by different lactate dehydrogenase enzymes in living organisms. Currently, 85% of the LA produced is consumed by the food-related industry, while the balance is used for nonfood applications, such as the production of biopolymers, solvents (John et al., 2009). L-lactic acid can be metabolized by enzyme action in the human body. However, the intake of D-lactic acid should be undertaken with caution: 100 mg/kg of body weight is the daily maximum stipulated for adult humans, and strictly no D-lactic acid or DL-lactic acid should be present in infant food, according to the FAO/WHO guidelines (Deshpande, 2002). Although the human body does not produce an enzyme for D-lactic acid,

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HO

OH L-(+)-lactic acid

H

CH3 O

HO

OH

D-(–)-lactic acid

Lactic acid

H3C

Molecular structure

Oxygen

Carbon

H

Hydrogen

Figure 2.2 Stereoisomers of lactic acid.

a small intake is considered safe because the high solubility of D-lactic acid promotes hydrolysis in the body fluid subsequently removed by the body’s excretion system. Most of the LA produced globally is made using the fermentation process. According to a review paper on LA bacteria fermentation (Reddy et al., 2008), there are about 20 genera in the phylum Firmicutes that encompass LA-producing bacteria; these include Lactococcus, Lactobacillus, Streptococcus, Leuconostoc, Pediococcus, Aerococcus, Carnobacterium, Enterococcus, Oenococcus, Tetragenococcus, Vagococcus, and Weisella. Of the many genera that contain LA-producing bacteria, Lactobacillus is the most significant, comprising around 80 species that produce LA (Axelsson, 2004). These include the species Lactobacillus amylophilus, Lactobacillus bavaricus, Lactobacillus casei, Lactobacillus maltoromicus, and Lactobacillus salivarius. Strains of Lactobacillus delbrueckii, Lactobacillus jensenii, and Lactobacillus acidophilus produce D-lactic acid and a mixture of the two stereoisomers concurrently (Nampoothiri et al., 2010). Some species of Lactobacillus have the ability to undergo fermentation using a variety of saccharines, as listed in Table 2.2. Although a bacterial organism and carbohydrate are the essential components in the fermentation process, the organism requires a variety of nutrients to ensure its healthy functionality, including B-vitamins, amino acids, peptides, minerals, fatty acids, nucleotide bases, and carbohydrates. The amounts are species-dependent and the source of these nutrients can be agricultural derivatives, such as corn steep liquor and yeast extract. LA bacteria are heterotrophic, which mean that they lack biosynthetic capabilities (Reddy et al., 2008). The addition of complex nutrients can significantly increase the cost of production. However, a higher purity LA is produced. In the LA fermentation process, the LA bacteria are grown under anaerobic conditions with low-energy production. Such low-energy

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Table 2.2 Respective Saccharines Fermented by Lactobacillus Species Produce Lactic Acid Lactobacillus

Saccharine

Lactobacillus delbreuckii subspecies delbreuckii Lactobacillus delbreuckii subspecies bulgaricus Lactobacillus helveticus Lactobacillus amylovirus Lactobacillus lactis Lactobacillus pentosus

Sucrose Lactose Lactose and galactone Starch Glucose, sucrose, and galactose Sulfite waste liquor

Table 2.3 Fermentation Patterns of Lactobacillus Genus (Reddy et al., 2008) Homofermentative

Ability to yield more than 85% lactic acid (LA) from glucose which is equivalent to fermentation of 1 mole of glucose to 2 mole of lactide acid while generating a net yield of 2 mole of ATP per molecule of glycose metabolized. Mostly LA is produced in this process Heterofermentative Yielding a lower amount of about 50% of LA accompanied with side products. Every mole of glucose generates 1 mole of LA, 1 mole of ethanol and 1 mole of carbon dioxide. A lower growth per mole for each mole of glucose metabolized due to only 1 mole of ATP is produced at every mole of glucose Rare heterofermentative A less known fermentative species which yields DL-lactic acid, acetic acid, and carbon dioxide

yield bacteria grow slowly compared to respiration-type microbes. LA bacteria survive well at temperatures of between 5
C and 45
C and mildly acidic conditions (pH 5.56.5). Reddy et al. (2008) divided the Lactobacillus genus into three groups according to their fermentation patterns (see Table 2.3). The products of each pattern are shown in Fig. 2.3. Fermentation of different types of carbohydrate-rich material varies the yield of LA (see Table 2.4). In addition to Lactobacillus bacteria there are other microbial sources—fungi such as Rhizopus

Figure 2.3 Metabolism of lactic acid bacteria (Reddy et al., 2008). Source: Published with permission of Elsevier.

Table 2.4 Yield of Lactic Acid (LA) Corresponding to Starchy and Cellulosic Materials Corresponding to Microorganism Substrate

Microorganism

LA yield

Wheat and rice bran Corn cob Pretreated wood Cellulose

Lactobacillus sp. Rhizopus sp. MK.961196 Lactobacillus delbrueckii Lactobacillus coryniformis ssp. Torquens Lactobacillus casei NRRLB-441 L. delbrueckii NCIM 2025, L. casei Lactococcus lactis ssp. ATCC 19435 L. lactis and L. delbrueckii Rhizopus oryzae, R. arrhizuso Lactobacillus amylovorous ATCC 33620 L. amylovorous NRRL B-4542

129 g/L 90 g/L 4862 g/L 0.89 g/g

Barley Cassava bagasse Wheat starch Whole wheat Potato starch Corn, rice, wheat starches Corn starch

Source: Published with permission of Elsevier.

0.870.98 g/g 0.90.98 g/g 0.771 g/g 0.930.95 g/g 0.870.97 g/g ,0.70 g/g 0.935 g/g

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oryzae also produce LA, but under aerobic conditions. However, fermentation of such fungi is not favorable, due to their slow growth and low productivity, while the significant agitation and aeration required lead to high energy costs for long-term operations (Jem et al., 2010). Despite the focus on using wild microorganisms for producing LA, a few attempts have been made to improve L-lactic acid yield through metabolic engineering, as summarized in Table 2.5.

Table 2.5 Modification of Strains for Better Yield of L-Lactic Acid (Narayanan et al., 2004) Strain Lactobacillus helveticus Lactobacillus plantarum

Modification

Inactivation of D-lactate dehydrogenase gene increases the amount of L-lactic acid twofold L-lactate dehydrogenase gene of Lactobacillus plantarum is isolated and cloned into Escherichia coli. This has increased the L-lactate dehydrogenase activity 13-fold Lactococcus lactis Increasing the number in lac operon that increases the L-lactate dehydrogenase results in slight increases in the yield of lactic acid (LA): • Operon: Functioning unit of genomic material containing a cluster of genes under the control of a single regulatory signal or promoter • Lac operon: lac operon is required for the transport and metabolism of lactose in enteric bacteria Lactobacillus D-lactate dehydrogenase gene was isolated and an johnsonii in vitro truncated copy of the gene was used to inactivate the genomic copy of the wild strain. Due to lowering L-lactate dehydrogenase activity rerouted pyruvate to L-lactate with increase of by-products such as acetaldehyde, acetoin, and diacetyl E. coli The dehydrogenase and phosphotransacetylase double mutants were able to grow anaerobically on glucose by lactate fermentation producing D-lactate. An L-lactate dehydrogenase gene is introduced results fermentation which yields L-lactate Rhizopus oryzae The mutant grows under limiting oxygen conditions with 5% wild-type alcohol dehydrogenase activity, which leads the pyruvate to form LA

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Most of the commercial fermentation processing of LA in batches requires 36 days to complete; sugar concentrations of between 5% and 10% are used (Garlotta, 2001). Many LA fermentation processes have been patented over the decades. Most of these patents are restricted in the disclosing of the fermentation process, as they also provide the LA separation technologies. In US patent 6 319 382 B1, by the inventor Norddahl (2001), whey protein is added as a nutrient substrate for the LA bacteria and protease is added to the fermenter to enable hydrolysis of protein to supply amino acids during the fermentation process. In addition, the aqueous medium in use consists of yeast extract, K2HPO4, MgSO4  7H2O, MnSO4  2H2O, Tween 80, lactose, and cysteine hydrochloride to ensure optimum reactivity of LA bacteria (Norddahl, 2001; Tsao et al., 1998; Robison, 1988). During the fermentation process, the pH of the aqueous slurry is monitored to maintain near-neutral mildly acidic conditions. The objective is to avoid the accumulation of LA in the fermentative medium, which can inhibit the productivity of the bacteria. Thus a continual addition of bases such as calcium hydroxide, sodium hydroxide, or ammonia can help to convert the generated LA into a lactate salt. The lactate salt can later be converted to LA by reaction with acids. According to Norddahl (2001), ammonia is preferable over other bases, because it has the advantage of providing a source of nitrogen nutrients to the bacteria. This has shown evidence of improved growth compared to sodium hydroxide. Most processes employ calcium hydroxide to control the pH of the aqueous mixture, including in the production process utilized by NatureWorks (Vink et al., 2010). Sulfuric acid is then added to the LA broth to recover the LA, resulting in the formation and precipitation of gypsum (i.e., calcium sulfate, CaSO4  2H2O). The gypsum is separated from the broth using a filtration method and this gypsum is a by-product, which can be sold as a construction material or a soil conditioner. It is estimated that up to 1 ton of gypsum is produced for every ton of LA yield (Garlotta, 2001). The LA broth from the fermenter needs to further undergo thorough separation before pure LA is recovered. Some approaches include electrodialysis, reverse osmosis, liquid extraction, ion-exchange acidification, ion-exchange purification, distillation, insoluble salt processes, or esterification. Henton et al. (2005) have comprehensively summarized the LA purification technologies and their respective advantages and disadvantages (see Table 2.6). Although there is no difference in recovering D-lactic acid and L-lactic acid, extreme conditions should be avoided (e.g., high temperatures), due to the high possibility of

Table 2.6 Lactic Acid Purification Technology (Henton et al., 2005)

Technology Electrodialysis

Feature

Advantages/ Disadvantages

Can be used to continuously 1. Does not require remove lactic acid (LA) acidification of (lactate ions) through a fermentation membrane driven by 2. Energy cost and capital electrical potential Reverse LA is continuously removed 1. Higher productivity due osmosis through a membrane to the ability to maintain a low acid level in the fermenter 2. Fouling of the membrane 3. Requires acidic pH stable organism Liquid LA is continuously removed 1. Suitable for continuous extraction from the fermentation or process and provides acidified broth by efficient removal from preferential partitioning many nonacidic into a solvent impurities 2. High cost of capital 3. Solvent loss costs Ion exchange The lactate salt is acidified 1. Eliminates the need to (acidification) by a strong acid ionadd a strong acid to the exchange resin fermentation 2. Cost of resin and issues of resin regeneration Ion exchange LA is removed from the 1. This is the solid (purification) aqueous solution by equivalent of t-amine complexing with an extraction technology amino-containing resin without the solvent loss issues 2. Regeneration of the resin 3. Cost and availability of the resin Distillation LA is separated from less 1. LA can be steam volatile components by distilled vacuum steam distillation 2. Significant purification must be done prior to distillation 3. Depending on conditions, some degradation and oligomerization can occur

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Table 2.6 Lactic Acid Purification Technology (Henton et al., 2005)—cont’d Advantages/ Disadvantages

Technology

Feature

Insoluble salt processes

The fermentation or 1. Simple process that purification process is run utilizes low-cost capital at a concentration that 2. The crystallization of exceeds the solubility of CaSo4 occludes the lactate salt (e.g., impurities and results in CaSO4), which is isolated relatively impure acid and acidified Lactate esters are prepared 1. Distillation and and the volatile esters are separation of esters distilled gives high-quality product 2. Requires reconversion to acid

Esterification

Source: Published with permission.

converting D-lactic acid and L-lactic acid into each other, thus forming a racemic mixture. High optical purity of L-lactic acid (.99%) is required for food and pharmaceutical applications in order to achieve the stringent requirements for oral intake. Selectivity of a single optical LA is preferable for quality control, because different optical LAs can affect the properties of PLA, such as melting point, mechanical strength, and degradability. Currently, NatureWorks owns the largest single LA production facility, with 180,000 MT produced per year using corn as the feedstock. The LA produced by NatureWorks is mainly used for conversion to Ingeo PLA. Meanwhile, Purac is the largest LA producer, and their products are widely used in the food, beverage, and pharmaceutical industries, as well as for producing PLA, primarily for surgical applications (e.g., pins, sutures, and screws). Purac is also involved in the copolymerization of LA with other monomers—glycolide, ε-caprolactone, or D,L-lactic acid. The company built a new LA plant in Thailand, which has been operating since 2007. The plant is designed to utilize locally harvested sugarcane as the feedstock, with an initial capacity of 100,000 MT. It is planned that the plant will be at full operating capacity in the near future. While LA is mainly produced using cheap agricultural

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feedstock, two companies still use the chemical synthesis method to produce a racemic mixture of LA. These companies are Musashino, in Japan, and Sterling Chemicals Inc., in the United States. Chemical synthesis and the ordinary fermentation processes undergo different reaction paths (Narayanan et al., 2004). These are outlined below. Chemical synthesis approach 1. Addition of hydrogen cyanide CH3 CHO 1 Acetaldehyde

HCN

catalyst

Hydrogen cyanide

! CH3 CHOHCN Lactonitrile

2. Hydrolysis by H2SO4 CH3 CHOHCN 1H2 O1 1=2H2 SO4 -CH3 CHOHCOOH 11=2ðNH4 Þ2 SO4 Lactonitrile

Sulfuric acid

Lactic acid

Ammonium salt

3. Esterification CH3 CHOHCOOH 1 CH3 OH - CH3 CHOHCOOCH3 1 H2 O Lactic acid

Methanol

Methyl lactate

4. Hydrolysis by H2O CH3 CHOHCOOCH3 1 H2 O- CH3 CHOHCOOH 1 CH3 OH Methyl lactate

Lactic acid

Methanol

Fermentation approach 1. Fermentation and neutralization C6 H12 O6 1

Carbohydrate

Fermentation

!

CaðOHÞ2

ð2CH3 CHOHCOO2 ÞCa21 1 2H2 O Calcium lactate

Calcium hydroxide

2. Hydrolysis by H2SO4 2ðCH3 CHOHCOO2ÞCa211 H2 SO4 - 2CH3 CHOHCOOH 1 CaSO4 Calcium lactate

Sulfuric acid

Lactic acid

Calcium sulphate

3. Esterification CH3 CHOHCOOH 1 CH3 OH - CH3 CHOHCOOCH3 1 H2 O Lactic acid

Methanol

Methyl lactate

4. Hydrolysis by H2O CH3 CHOHCOOCH3 1 H2 O- CH3 CHOHCOOH 1 CH3 OH Methyl lactate

Lactic acid

Methanol

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Commercial purified LAs are sold at concentrations between 50% and 80%. Typical food-grade LAs differ in concentration and depend on the carbohydrates blended with them, which are mainly added to improve taste, nutrition, or as preservatives. Galacid, which is produced in food grades by Galactic S.A., one of the major manufacturers of LA in Europe, has nutritional energy data as provided in Table 2.7. Industrial LA is sold in aqueous solution at 80%88% purity for small-scale applications, such as terminating agents for phenol formaldehyde resins, alkyd resin modifiers, solder flux, lithographic and textile printing developers, adhesive formulations, electroplating and electropolishing baths, or detergent builders. The pharmaceutical grade of LA is sold at US$10001500 per ton while the industrial grades can be 20% less expensive depending on the area of application. Many of the new LA production facilities in China have yet to prove their feasibility in the short term due to the maturity of the implementation of the high-efficiency fermentation process as well as the local market demands of PLA. Nevertheless, the multiapplications of LA will maintain its market interest on a long-term basis.

2.2.1 Laboratory-Scale Production of Lactic Acid Fermentation is the most common approach used for the production of LA. The method that is outlined here (Ohara et al., 2003) can be utilized to synthesize LA in lactate form for prepolymer LA production [See Box 2.1]: As shown in the step 3, the ethanol is used to react with fermented LA via an esterification reaction to form ethyl lactate (generally known as lactate ester). The reason lactate ester is preferable over LA for conversion into LA prepolymer is because LA has a corrosive nature. Therefore synthesizing PLA from lactic ester can help to reduce costs by avoiding the need to invest in corrosive-resistant reactors and equipment. This represents a significant cost reduction in the long term.

Table 2.7 Nutritional Data of Galacid Nutritional Data Basis: per 100 g Energy (kJ) Total carbohydrates

Concentration 50% 745760 49.550.5

80% 11961211 79.580.5

85% 12711287 84.585.5

88% 13171332 87.588.5

90% 13471362 89.590.5

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Box 2.1 Method for Synthesis of Lactic Acid in Lactate Form 1. First, 5 L of culture medium is prepared, which consists of 500 g glucose, 100 g yeast extract, and 100 g polypeptone. The medium is sterilized using an autoclave and finally a microbe species from one of the flowing genera is implanted: Lactobacillus, Streptococcus, Rhizopus, Bacillus, or Leuconostoc. 2. The mixture is cultured at a temperature of 37
C, with the pH maintained at 7.0 using 6 N ammoniawater. The culture takes 15 hours to complete. 3. The culture is concentrated using 1000 g of ethanol and refluxed for 3 hours at between 90
C and 100
C in a condenser to obtain ethyl lactate. 4. The inconsumable ammonia is separated using a gas-washing bottle connected at the end of the condenser, cooling with ice water. This ammonia entrapping system is able to collect up to 98% of the ammonia. 5. The remaining reaction mixture is maintained at 80
C to vaporize the 750 g of unreacted ethanol by distillation. 6. The reaction mixture is further raised to a temperature of 120
C to remove the water. 7. After the removal of water, the reaction mixture undergoes a distillation process at 50 mmHg at a liquid temperature of 70
C100
C, to yield 650 g of purified ethyl lactate for the polycondensing process.

2.3 Lactide and Poly(Lactic Acid) Production Lactide is an intermediate substance in the production of PLA via the ROP method. As can be seen from Fig. 2.4, although both DP and ROP involve the step of producing LA prepolymer, the polymerization through lactide formation can be done without the application of coupling agents. The purpose of the coupling agents is to increase the molecular weight of the PLA. In fact, the LA prepolymer is lowmolecular-weight PLA (Mw 5 10005000). This low-molecular-weight PLA is unusable—it possesses weak, glassy, and brittle properties. According to Garlotta (2001), the formation of low-molecular-weight PLA for direct reaction of prepolymer is mainly used because of the lack of reactivity of the end groups, excess water, and high viscosity of the polymer melt once polymerization is completed. ROP of lactide was first performed by Carothers in the mid-1900s, and later patents relating

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Figure 2.4 Reaction pathways for producing poly(lactic acid) from lactic acid. Published with permission of Elsevier.

to this technology by DuPont kick-started the mass production of PLA. Lactide molecules undergo either anionic or cationic ring polymerization, depending on the selection of initiator type. The formation of free radicals with the action of initiators upon the functional groups elevates the propagation of chain reaction; consequently, a highmolecular-weight polymer is formed.

2.3.1 Review of Lactide Production Technology Lactide production technologies have been in use since the 1930s, with a related publication by Carothers et al. (1932) about the reversible polymerization of six-membered cyclic esters. Lactide technology then underwent a period of inactivity because the purity of lactide was insufficient for large-scale production. Lactide technology did well after DuPont developed a purification technique. This ultimately led toward mass-scale production by NatureWorks. This section mainly focuses on the mass-scale lactide production as developed by CargillDuPont (currently known as NatureWorks) in the early phases, as well as some related lactide technologies. US Patent 5 274 073, entitled “Continuous Process For Manufacture of A Purified Lactide,” as filed by Gruber et al. (1993), describes a method of lactide production that can be summarized into the steps shown in Fig. 2.5. Initially, the crude LA is fed into an evaporator.

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Feed crude lactic acid to an evaporator continuously

Remove water or solvent from crude lactic acid

Discard or recycle removed water, solvent of condensation by-product

Feed concentrated lactic acid to a pre polymer reactor

Polymerize concentrated lactic acid to form a pre polymer by removing water

Feed pre polymer to a lactide reactor

Recycle or discard removed water, solvent, or condensation by-product contaminated with lactic acid

Remove and recycle or discard highboiling unreacted polymer as liquid from lactide reactor

Simultaneously feed catalyst to a lactide reactor

Remove crude lactide as a vapor from lactide reactor

Partially condense crude lactide in a condenser

Remove uncondensed water and lactide impurity as a vapor and recycle or discard

Feed condensed crude lactide to a distillation system

Purify lactide in the distillation system

Remove water and lactide acid impurities as a distillate/overhead stream, recycle or discard

Remove purified lactide as a high-boiling bottom stream from the distillation system

Feed purified lactide as a liquid directly to a polymerization system

Polymerize lactide to polylactide

Figure 2.5 Process flow of lactide production.

Generally, this is commercially produced LA, consisting of 15% LA with 85% water. This solution is due to the fact that the fermentation process was carried out in an aqueous medium. The evaporator is used to vaporize the water as the top product, while the remainder is the concentrated LA. LA produced by fermentation contains other impurities mixed with the enantiomers of L- and D-lactic acid. These impurities, including carbohydrates, proteins, amino acids, salts, metal ions,

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Figure 2.6 Lactide stereocomplex. Published with permission of Elsevier.

Figure 2.7 Condensation polymerization of lactic acid.

aldehydes, ketones, carboxylic acids, and esters of carboxylic acids, can affect the production quality of lactide, and subsequently of PLA. Hence, on a case-by-case basis, an evaporator can be designed to fulfill the purity requirement. Nevertheless, a conventional evaporator, such as a multiple effects evaporator, a wiped film evaporator, or a falling film evaporator, can provide a basic separation to the crude LA. The operation of the evaporator works best at below atmospheric pressure, in order to reduce the consumption of heating energy while, importantly, avoiding a racemic stereocomplex of D-lactide, L-lactide, or mesolactide (see Fig. 2.6), which tends to cause quality issues when undergoing polymerization to form polyD, L-(lactic acid). Upon exiting the evaporator, the crude LA has been concentrated to over 85%. For the next stage, the concentrated LA is transferred into a prepolymer reactor. The prepolymer reactor is actually a second evaporator, which further removes water from the LA. At the same time, the condensation polymerization takes place to form PLA with an optimum molecular weight of 4002500. When LA has undergone condensation polymerization, the alkoxy group is reacted with the hydrogen cleaved from the hydroxyl group of the nearest LA molecule. Therefore the remaining products are a long LA linkage and excess water molecules. The removal of water is important in order to ensure that the reaction proceeds toward the right side of the reaction path shown in Fig. 2.7. During the polymerization reaction a depolymerization reaction also takes place due to the inherent equilibrium of the reaction scheme. The equilibrium reaction suggested by Gruber et al. (1993) is shown in Fig. 2.8. Gruber et al. (1993) assert that the prepolymer reactor can be designed into a single system, which can facilitate both the

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Figure 2.8 Equilibrium reaction of polymerization and depolymerization reaction of lactic acid (Gruber et al., 1993).

concentrating of the LA feed while polymerizing the LA into oligomer LA. However, split units for evaporation and prepolymerization stages are preferable for controllability. The recovery of LA can be done more effectively when the water separated from the crude LA is recycled back to prevent loss of feed material. At the same time, a high concentration of LA at reduced volume in the prepolymerization stage is helpful to shift toward polymerization rather than depolymerization, for a better yield of oligomer LA. The oligomer LA, which has also been described previously as the prepolymer, is fed into the lactide reactor. Many suitable types of catalyst can be simultaneously fed with the prepolymer stream into the reactor. Catalysts such as metal oxides, metal halides, metal dusts, and organic metal compounds derived from carboxylic acids are commonly used. Based on the reaction scheme set out in Fig. 2.8 the depolymerization reaction (as shown in the bottom part) immediately reaches equilibrium. The reaction is carried out at high temperature to enable the crude lactide to vaporize and be continuously removed from the reactor, thus shifting the reactor toward the depolymerization reaction. This follows Le Chatelier’s principle that the lactide reactor yield is higher when there is a reduced amount of lactide, in order to seek reaction equilibrium in the lactide reactor. However, the unreacted long chain of PLA, with its high boiling point, remains in the bottom of the reactor as it is purged. Such product can be recycled back into either the prepolymer reactor or the lactide reactor. The unreacted high-molecular-weight

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PLA undergoes transesterification to form a shorter chain of oligomer, which is a source of lactide for the reactor as well. The use of such a recycle stream is not limited to improving the recovery of valuable feed material; it also helps to improve the production yield and it reduces the cost of waste treatment. As mentioned earlier, the stereocomplex composition of the lactide produced is dependent on the initial crude LA feed, the catalyst used, and the processing parameters (i.e., temperature and pressure). Thus the crude lactide vapor consists of a mixture of L-lactide, D-lactide, and meso-lactide. Some low-volatility products, such as water, LA, and dimer LA, are also contained in this stream. A partial condenser can be used to partly condense the low-boiling-point components, such as water and LA, prior to undergoing distillation. A conventional distillation column is fitted to separate the feed into three component streams. The distillate or overhead low-boiling components are water and LA, and the other low-molecular-weight by-products from the reactions of the prepolymer reactor and lactide reactor. The bottom stream consists of products with lower volatility than lactide, such as LA oligomers with more than three repeating units. Both overhead and bottom products are recyclable in order to achieve a higher conversion of LA into lactide. Lactide is simultaneously withdrawn from the side stream as the third component. The purity of the lactide is considered acceptable at a concentration of 75%; with a higher purity of lactide it is very important to form a high-quality polylactide. Ohara et al. (2003), in US Patent 6 569 989, disclosed a more detailed process for synthesizing lactide (see Fig. 2.9). LA is polycondensed by stepwise heating at 130
C220
C at different stages, while the pressure of each stage is reduced to 5 mmHg, yielding PLA prepolymer of molecular weight 10003500. This multistage process can be further defined at different temperatures, where the first stage is at 135
C, the second stage 150
C, the third stage 160
C, the fourth stage 180
C, and finally the fifth stage at 200
C. A metal type of catalyst, as summarized in Table 2.8, is added during the reaction to improve selectivity while reducing the reaction time. Since both polymerization and depolymerization take place simultaneously, a similar catalyst is also suitable to be applied in lactide production. Hence a metal catalyst is added with the reaction conditions of 200
C and pressure of 5 mmHg to produce lactide. The catalyst is preferably applied at 0.0010.01 wt.% with respect to the fresh or crude LA or lactide to the reactor.

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Source of pentose and/or hexose derived from starch, agricultural biomass, etc. Culture medium containing microbes for fermentation

Lactic fermentation

Addition of ammonium lactate

Recycling of ammonia

Esterification

Recycling of alcohol

Lactate ester

Polycondensation and dealcoholization

Lactic acid prepolymer

Depolymerization and intramolecular esterification

Lactide

Ring-opening polymerization

Polylactic acid

Figure 2.9 Steps to produce poly(lactic acid) from the initial fermentation process (Ohara et al., 2003).

2.3.2

Polymerization and Copolymerization of Lactide

Most of the processes in industry employ ROP of lactide to achieve high-molecular-weight PLA. Although the DP reaction path appears to be the simplest to polymerize monomer LA, the yield of PLA is relatively low in molecular weight (,5000) and weak in mechanical

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Table 2.8 Type of Catalyst for Polymerization and Depolymerization of Lactic Acid Metal Group

Type

IA

Hydroxide of alkali metal

IIA IIB IVA

IVB

VA VIIA

Catalyst

Sodium hydroxide, potassium hydroxide, lithium hydroxide Salt of alkali metal with Sodium lactate, sodium acetate, weak acid sodium carbonate, sodium octylate, sodium stearate, potassium lactate, potassium acetate, potassium carbonate, potassium octylate Alkoxide of alkali metal Sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide Calcium salt of organic acid Calcium acetate Zinc salt of organic acid Zinc acetate Tin powder, organic tin type Tin lactate, tin tartrate, tin catalyst except dicaprylate, tin dilaurylate, tin monobutyltin diparmitate, tin distearate, tin dioleate, tin α-naphthoate, tin β-naphthoate, tin octylate Titanium-type compound Tetrapropyl titanate, zirconium and zirconium-type isopropoxide compound Antimony-type compound Antimony trioxide Manganese salt of organic Manganese acetate acid

properties. Consequently, its applications are limited. The ring polymerization is conducted in a solvent-based system with anionic and cationic initiations. This has the advantages of high reactivity and selectivity as well as low racemization and impurity levels. Trifluoromethane sulfonic acid and methyl trifluoromethane sulfonic acid are the cationic initiators used to polymerize lactide (Garlotta, 2001). Such cationic ROP is carried out at a low temperature (100
C), and the resulting PLA product is an optically pure polymer. The used of a primary alkoxide, such as potassium methoxide, as the anionic initiator can produce a ,5% racemization of PLA. Nevertheless, the anionic lactide polymerization

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requires a higher reaction temperature, typically for weaker bases such as potassium benzoate and potassium phenoxide, which initiate its reactivity at 120
C. Although the anionic and cationic initiations as described above have the advantage of producing low racemization PLA at a lower temperature, the reaction process needs to be conducted in a solvent system in a dilute condition, in order to control its reactivity and the sensitiveness for the presence of impurities. The anionic and cationic initiators also possess high toxicity. These aspects narrow the application of anionic and cationic initiators in lactide polymerization. In the large-scale PLA industry, the metal catalyst approach is preferable, with its fast and high yield in lactide polymerization. The highly effective catalyst is merely applied at a low level (,10 ppm), which helps to ensure the safety of PLA when used in food packaging and in biomedical applications. Polymerization of lactide yields high molecular weight (. 250,000) with the use of stannous octoate (commonly known as tin octoate). The catalytic ROP reaction is also applicable for copolymerization of lactide with other monomers such as glycolide and ε-caprolactone. Many of the catalyst systems can be used to polymerize lactide, including transition metals such as aluminum, zinc, tin, and the lanthanides. These metal oxides and complexes have different degrees of conversion and high racemization. Of the metal compounds listed in Table 2.8, tin or stannous (Sn) complexes are very important for the bulk polymerization of lactide, especially tin (II) bis-2-ethylhexanoic acid (also known as tin octoate). Tin octoate is preferred due to its solubility in molten lactide; thus it achieves a high conversion of .90% with high selectivity by producing less than 1% racemization. Such high conversion reactivity is favorable for good quality control in terms of mechanical and biodegradability properties. This is important for LA polymers used for biomedical applications because only the L enantiomer of LA is consumable by the living cell due to the lack of an enzyme in the body to consume D-lactic acid after hydrolysis into its monomer. Meanwhile, substantial racemization can significantly affect the crystallinity rearrangement structure compared to a single isomer, thus lowering the mechanical properties. Lactide polymerization with the addition of tin octoate is proposed via the coordinationinsertion mechanism, as shown in Fig. 2.10 (Henton et al., 2005). The tin catalyst initiates the ring-opening reaction by attacking the nearest double-bond oxygen of the lactide. The hydroxyl and nucleophilic species simultaneously react with the ringopened radical and finally form a water molecule as a by-product to

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Figure 2.10 Coordinationinsertion chain growth reaction scheme of lactide to poly(lactic acid) using tin octoate: R, growth of polymer chain (Henton et al., 2005).

Figure 2.11 Copolymerization of glycolide and caprolactone, respectively, with lactide using tin octoate (Henton et al., 2005).

achieve a steady state. The polymerization process produces a low racemic mixture, high productivity, and high-molecular-weight PLA. The typical polymerization conditions are: 180
C210
C, at tin octoate concentrations of 1001000 ppm, and 25 hours to achieve 95% conversion. The tin octoate catalyst is also applicable for copolymerization of caprolactone and glycolide, with the reaction scheme as shown in Fig. 2.11. The residual catalyst in the above polymerization process can cause unexpected problems in terms of processing degradation, hydrolysis, or toxicity. Thus the reactivity of the catalyst is deactivated with the addition of phosphoric or pyrophosphoric acid. The catalyst can also be

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separated by reaction with sulfuric acid by precipitation. The catalyst levels in the PLA or its copolymer should be reduced to 10 ppm or less to ensure the quality for end-user applications (Hartmann, 1998).

2.3.3

Lactide Copolymer

Lactide can be copolymerized with glycolide monomer to improve the biological compatibility and good absorption time when implanted in living tissue. Typical applications of lactideglycolide copolymers, such as surgical sutures, should contain .80% glycolide by weight. This is because when the glycolide in the copolymer is less than 80% the crystallinity is lower and so it lacks tensile strength and retention in applications. Low glycolide content in a copolymer is not favorable because the predominance of lactide in the suture lowers the rate of absorption by living tissue. The copolymerization of lactide and glycolide shares a similar process to the polymerization of optically active lactide alone. Stannous octoate is also used as a catalyst in the copolymerization reaction, as shown in Fig. 2.11. A high glycolide-content copolymer is achievable through a two-step reaction process. According to Okuzumi et al. (1979), the first stage involves polymerization at 65%75% of optically active lactide with the remaining glycolide monomer. In the second stage, a high content of monomer at 80%90% glycolide is used in the copolymerization reaction. Okuzumi et al. (1979) found that if the reverse is attempted, the resulting lactideglycolide copolymer has low molecular weight and forms an amorphous polymer, which makes it inappropriate for surgical sutures, which need a high-strength fiber. This observation is summarized in Table 2.9. Lactide is also copolymerized with ε-caprolactone monomer to produce biomaterials for the manufacture of surgical implants and drug carriers. The copolymerization of lactidecaprolactone follows a similar reaction path as lactideglycolide. The preference is for a random copolymer comprising of 5570 mol.% of lactide and 3045 mol.% of caprolactone for application as a pharmaceutical carrier (Bezwada, 1995). Although the above-mentioned lactideglycolide and lactide caprolactone copolymers are suitable for making medical devices with excellent properties, such as high strength, stiffness, and long breakingstrength retention, copolymerization of lactide with dioxanone monomer is able to enhance the elongation properties of lactide for toughened applications, such as absorbable medical devices, foams for tissue scaffolds, and hemostatic barriers. The production of lactidedioxanone copolymer is also undertaken in a two-step reaction (see Fig. 2.12).

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Table 2.9 Tensile Strength of LactideGlycolide Copolymer With Respect to the Composition Wt.% of LactideGlycolide First Stage Copolymerization

Second Stage Copolymerization

Final Copolymer Composition

40/60 70/30 70/30 70/30 87/13 87/13 78/22 78/22 78/22

0 12/88 12/88 12/88 12/88 12/88 12/88 12/88 18/72

40/60 35/65 40/60 45/55 35/65 50/50 35/65 45/55 50/50

Tensile Strength (psi) 3 103

53 64 67 72 60 58 71 63 58

Initially, the lactide is reacted with a small amount of p-dioxanone monomer at 100
C130
C for 48 hours. This is followed by increasing the temperature to 160
C190
C for 14 hours to further copolymerize lactide with the long-chain poly(p-dioxanone) prepared in the first step. This finally produces a high-strength, tough, and elastomeric biopolymer with 3050 mol.% of lactide. The low-toxicity and high-selectivity stannous octoate is used in the copolymerization process to produce a highmolecular-weight moxanone copolymer of 60,000150,000.

2.3.4 Quality Control The mass-scale production of PLA is most commonly used to make domestic consumer products, such as packaging or bottles, which come into contact with food. For these PLA products quality control no longer limits mechanical properties, as it does for commodity polymers (polyethylene, polypropylene, polystyrene, etc.). However, manufacturers need to carefully classify the extent of lactide, and specifically D-lactic acid, in the final product. NatureWorks, as the largest producer of PLA, has set up standard testing procedures for the firms that produce items using their Ingeo products. These testing procedures are summarized below. Although these tests were developed by NatureWorks LLC, their application is not limited, and they can be widely used throughout the PLA industry.

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Figure 2.12 Copolymerization reaction steps of lactidedioxanone copolymer (Bezwada, 1995).

2.3.5 Quantification of Residual Lactide in Poly(Lactic Acid) (NatureWorks L.L.C., 2010b) The determination of lactide composition in PLA is conducted by gas chromatography (GC) using a flame ionization detector (FID). This GC/FID method is only able to detect residual lactide in the range 0.15 wt.%. Although the detection range is narrow, it is still

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within the concentration 3 wt.% of lactide monomer found in PLA at 180
C, as well as after the devolatilization of PLA, when the concentration can further reduce to ,0.3 wt.%. As mentioned earlier, the lactide monomer consists of three stereoisomers: L-lactide, D-lactide, and meso-lactide. The GC method is only able to detect two lactide peaks with respect to the meso-lactide and the D-lactide or L-lactide (detected in a single peak). Meso-lactide has the earliest eluting peak, while the following eluting peak represents the coexisting Dlactide and L-lactide. The GC/FID method starts with the preparation of four solutions, namely (1) internal standard stock solution, (2) lactide standard stock solution, (3) lactide working standard solution, and (4) PLA samples solution. The methods of preparation are summarized in Table 2.10. Methylene chloride is the solvent used to

Table 2.10 General Procedures for Preparation of Standard and Poly (Lactic Acid) Samples Solution for Gas Chromatography/Flame Ionization Detector (GC/FID) Testing for Determination of the Presence of Lactide Residual Preparation of Solution General Procedure Internal standard stock solution (IS)

The solution is prepared by adding 2,6-dimethyl-γ-pyrone with methylene chloride under dilute condition Lactide standard stock The solution is prepared by adding a high-purity solution (LS) L-lactide into methylene chloride under dilute condition Lactide working standard The solution is prepared by mixing methylene solution (LW) chloride with IS and LS. A small amount of acetone is added and diluted with cyclohexane. This solution is analyzed using GC/FID PLA samples solution The solution is prepared to determine the composition of lactide in the PLA sample. First, a small known amount of PLA is added with the IS solution and diluted with methylene chloride as solution #1. Solution #1 is added with a small amount of acetone and diluted with cyclohexane to become solution #2. Solution #2 is filtered and analyzed using GC/FID

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dissolve PLA and release the free lactide. The free lactide remains in the methylene chloride while excess cyclohexane is added to precipitate the PLA. Then the supernate solution is filtered and injected into the GC and is finally detected by the FID. The selection of the GC injection temperature is crucial—it must be 200
C to avoid the possibility of reformed lactide due to the presence of low-molecularweight LA oligomers in the supernate. 2.3.5.1 Calculations 1. The calculation of residual lactide as below relates to a DB-17 ms capillary column (Agilent J&W), and is also equivalent to (50%-phenyl)-methylpolysiloxane:  RRF 5

Peak area of both ᴅ- and ʟ-lactide standard Amount ðgÞ of ᴅ- and ʟ-lactide   Amount ðgÞ of IS 3 Peak area of IS



2. The weight of D- and L-lactide (g) in the sample can be determined according to the following equation:  Total D- and L- lactide ðgÞ 5

Peak area of both ᴅ- and ʟ-lactide in sample RRF   Amount ðgÞ of IS 3 Peak area of IS

(2.1) 3. The weight percentage (wt.%) of total D- and L-lactide present in the sample is calculated using the following equation:

  ᴅ- and ʟ- lactide ðgÞ 3 100 wt:% D- and L- lactide in sample 5 Sample weight ðgÞ

(2.2) 4. The weight of meso-lactide (g) in the sample can be determined according to the following equation: meso-lactide ðgÞ 5

  Peak area of meso-lactide in sample RRF   Amount ðgÞ of IS 3 Peak area of IS

(2.3)



80

POLYLACTIC ACID 5. The weight percentage (wt.%) of meso-lactide present in the sample is calculated using the following equation:   meso- lactide ðgÞ wt:% meso- lactide in sample 5 3 100 Sample weight ðgÞ (2.4) 6. Total both the D- and L-lactide and meso-lactide to obtain the wt.% of residual lactide monomer in the PLA. 7. The prescribed GC/FIB testing method has evaluated its precision of 1.9% relative standard deviation to detect lactide in PLA.

2.3.6 Quantification of D-Lactic Acid Content in Poly(Lactic Acid) (NatureWorks L.L.C., 2010a) The evaluation of D-lactic acid presence is very important, especially if the PLA product will be in contact with food or is a biological implant. The daily allowable intake of D-lactic acid in adult humans is ,100 mg/kg and no D-lactic acid must be found in infant food. The residual of D- and L-lactic in the PLA samples can be detected using the chiral gas chromatography method, together with an FID. In this method, the samples are initially hydrolyzed in methanolic potassium hydroxide and this is followed by acidification under strong acid to catalyze the esterification reaction. Then, methylene chloride and water are added to the acidified solution, which separates into a double layer—an organic layer containing methyl lactate enantiomers dissolved in methylene chloride at the bottom and the nonorganic water as the top layer. The bottom organic layer is collected and analyzed using a GCFID system (see Table 2.10). The procedure for preparing PLA samples for testing is shown in Box 2.2. The separation of methyl lactate enantiomers is recommended using an Agilent J&W CycloSil-B column, which is 30% hepatkis (2,3-di-O-methyl-6-O-t-butyl dimethylsilyl)-β-cyclodextrin in DB-1701— stationary phase. β-Cyclodextrin is suitable for chiral separation due to the fact that its cyclic oligosaccharide units form inclusion complexes with different equilibrium constants with respect to methyl lactate enantiomers, leading to easy GC separation. This method has a wide detection range of 0.05%50% D-lactic acid in PLA.

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Box 2.2 Procedure for Preparing Poly(Lactic Acid) Samples for Testing 1. PLA sample is dissolved in methanolic potassium hydroxide solution at 65
C. 2. Sulfuric acid is added to the sample solution and heated to 65
C again. 3. Deionized water and methylene chloride are added. 4. The liquid sample is left to separate into two layers. 5. The bottom layer of the sample is drawn up and analyzed with GCFID.

2.3.6.1 Calculations 1. The relative percentages of D- and L-lactic acid enantiomers present in PLA are calculated as follows: 

Area of methyl ᴅ-lactate peak % D-lactide 5 Area of methyl ᴅ-lactate peak 1 Area of methyl ʟ-lactate peak



3 100%

(2.5) 2. The prescribed GCFIB testing method has an evaluated precision of ,1% relative standard deviation to determine D-lactic acid in PLA.

2.4 Catalysts for Polymerization of Poly(Lactic Acid) 2.4.1

Direct Polycondensation Route

It is well known that there are two common synthesis routes to produce PLA, which are the ROP of lactide and production of PLA through DP of LA. Although the DP of LA to produce PLA is a singlestep polymerization reaction, the poor process control of PLA molecular weight produced using the DP route makes it less favorable in the industrial production of PLA. In general, the ROP route has been commonly applied in industrial PLA production due to its ease of polymerization processing control, although its requires extra reaction steps.

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In the past few decades, numerous researches have been conducted to improve DP by obtaining high-molecular-weight PLA polymers. A new synthesis method of poly(L-lactic acid) has been developed by Moon et al. (2000) and Moon et al. (2001), to increase the molecular weight of poly(L-lactic acid) by introducing the melt polymerization reaction of LA prior to the solid-state polycondensation process. They had successfully produced the poly(L-lactic acid) polymer with high molecular weight, which exceeded 100,000 Da, after the melt polymerization and solid-state polycondensation reaction by using stannous chloride with p-toluenesulfonic acid (SnCl2/p-TSA) system as catalyst. PLA polymer is one of the most important polymers used in the biomedical and food packaging industries due to its bio-based and biodegradable nature and being environmentally bioabsorbable by converting into carbon dioxide and water. However, the poor mechanical properties such as toughness and thermal stability have limited its application in various industries. Wu et al. (2008) prepared poly(L-lactic acid)/silicon dioxide (SiO2) nanocomposites using in situ melt polymerization of L-lactic acid in acidic silica sol. Stannous chloride (SnCl2  2H2O) and toluene-p-sulfonic acid (TSA) have been used as binary catalysts during in situ melt polymerization to induce the activity of L-lactic acids. The SiO2 nanoparticles were chemically grafted on the L-lactic acid oligomers by in situ melt polymerization. In addition, the production of poly(L-lactic acid) using a stannous chloride-p-TSA system as catalyst is well known to be hazardous due to the stannous chloride-p-TSA tending to remain in the produced poly(L-lactic acid). Stannous chloride-p-TSA catalyst is toxic and is very hard to remove from the produced poly(L-lactic acid), causing its application to be limited in the biomedical and food packaging industries. Ren et al. (2013) replaced the stannous chloride-p-TSA with a green catalyst, macroporous resin Amberlyst-15 as catalyst in melt polycondensation reaction of L-lactic acid. Unlike the stannous chloride-p-TSA catalyst system, Amberlyst-15 is a nontoxic solid acid which can also be conveniently separated from the poly(L-lactic acid) prepolymer by a simple filtration method. The nontoxic Amberlyst-15 catalyst exhibits good catalytic performance, is easy to obtain, cheap in price, and can also be reused three times as recovered catalyst with almost identical catalytic activity during the reaction. The molecular weight of poly(L-lactic acid) prepolymer produced using Amberlyst-15 was found to reach 46,000 Da. This finding also indicates that Ambelyst-15 catalyst is not only safer than the stannous chloride-p-TSA catalyst system, it also showed very similar catalytic activity in melt polymerizing the L-lactic acid into poly(L-lactic acid) prepolymer.

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Ajioka et al. (1995) found that the organic sulfonic acids have been commonly used as an effective catalyst in the solution polycondensation of L-lactic acid in producing the poly(L-lactic acid) with considerable molecular weight. Similar work has also been conducted by Takenaka et al. (2017), who produced poly(L-lactic acid) with higher molecular weight through melt polymerization and solid-state polymerization reaction with dodecylbenzenesulfonic acids as the catalyst. LA initially underwent the bulk melt polymerization reaction at an annealing temperature of 80
C110
C using 0.7 wt.% dodecylbenzenesulfonic acid as catalyst to produce the poly(L-lactic acid) prepolymer with a molecular weight higher than 3000 Da. The prepared poly(L-lactic acid) prepolymer was subjected to a solid-state polycondensation process at a temperature of 140
C to produce poly(L-lactic acid) polymer with molecular weight up to 115,000 Da (Takenaka et al., 2017). They also found that dodecylbenzenesulfonic acid is the best catalyst among all aromatic sulfonic acids to provide and keep the catalytic activity throughout the long reaction time solid-state polycondensation process. In addition, the decomposition temperature of dodecylbenzenesulfonic acid is the highest (exceeding 200
C) in comparison to other sulfonic acids in which the decomposition temperature is around 150
C. The long reaction time of the polycondensation reaction could cause the other sulfonic acids to decompose and lose their initial catalytic activity. Bai and Lei (2007) investigated the effect of various types of organic acid anhydride catalysts, such as acid anhydrides cis-butenedoic anhydride, pyromellitic dianhydride, and phthalic anhydride on the polycondensation of LAs to produce PLA. Their results showed that the application of these organic acid anhydride catalysts in the bulk polycondensation reaction provided a positive effect by obtaining poly(D,L-lactic acid) polymers with average molecular weights in the range of 70,00090,000 Da in a high yield of PLA products. Huang et al. (2014) successfully synthesized poly(L-lactic acid) and poly(D-lactic acid) with high molecular weights of up to 120,000 Da and 100,000 Da using melt polycondensation and solid-state polycondensation with biogenic creatinine as catalyst, as shown in Fig. 2.13. The polymerization of PLA via melt polycondensation and solid-state polycondensation was stereochemically controlled throughout the whole polymerization process by producing poly(L-lactic acid) and poly(D-lactic acid) with high constant values of isotacticity up to 97.8%99.4%. Furthermore, the degradation temperature of PLA synthesized with melt and solid-state polycondensation with biogenic creatinine catalyst was also observed to be at least 100
C higher than the degradation temperature of PLA synthesized with catalyst SnCl2  2H2O.

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Figure 2.13 The production of poly(L-lactic acid) and poly(D-lactic acid) via melt and solid-state polycondensation of L-lactic acid and D-lactic acid using creatinine catalyst. Adapted from Huang, W., Cheng, N., Qi, Y., Zhang, T., Jiang, W., Li, H., et al., 2014. Synthesis of high molecular weight poly(l-lactic acid) and poly(d-lactic acid) with improved thermal stability via melt/solid polycondensation catalyzed by biogenic creatinine. Polymer 55, 14911496, with permission from Elsevier.

Pivsa-Art et al. (2013) synthesized poly(D-lactic acid) from two steps with direct polymerization of D-lactic acid using 2-naphthalenesulfonic acid (2-NSA) as catalyst. Initially, the D-lactic acid were melt polymerized with esterification with the presence of 2-NSA as catalyst to produce the poly(D-lactic acid) prepolymer. The produced poly(D-lactic acid) prepolymer was further subjected to solid-state polycondensation under high temperature with the pressure reduced continuously. They successfully synthesized the poly(D-lactic acid) to satisfy the thermal property (decomposition temperature of 255
C) and moderate average molecular weight of 33,300 Da. On the other hand, the synthesis method of poly(L-lactic acid) via DP reaction under vacuum condition in the absence of catalyst, solvents, and initiators was conducted by Achmad et al. (2009). They claimed that the uncatalyzed direct polymerization of L-lactic acid is a second-order reaction mechanism. This is attributable to the L-lactic acid itself being a strong acid and it can act as a catalyst during the polymerization reaction under vacuum conditions at polymerization temperatures of 150
C250
C. The molecular weight of poly(L-lactic acid) polymer produced under vacuum condition reached up to 90,000 Da at a polymerization temperature of 200
C after 89 hours of the polycondensation process. In addition, the activation energy for direct polymerization without catalyst is found to be higher the ring-opening polymerization with catalyst.

2.4.2 Ring-Opening Polymerization Route The ring-opening polymerization of lactide reaction route is a living polymerization method which is currently gaining attention from industries in the production of polylactide due its better reaction control in producing

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high-molecular-weight polylactide. The production of polylactide with high molecular weight in industry is commonly carried out using the ROP of L,L-lactide reaction with stannous octoate [Sn(Oct)2] as catalyst (Jing et al., 2006). Stannous octoate is the most commonly applied catalyst during ROP of L,L-lactide in industrial production of polylactide. This is due to the high polymerization rate, efficient activity in ROP of lactides, and also approval from the Food and Drug Administration (FDA) for biomedical industrial applications (Karidi et al., 2015). Zhang et al. (1994) investigated the effect of using hydroxyl and carboxylic acid substances such as alcohol as a cocatalyst in the ROP reaction of lactide with stannous octoate as the catalyst. They found that the production of polylactides from stannous octoate-catalyzed ROP with a different coinitiator could affect the molecular chains of polylactides, producing either linear or branched polymer chains with various molecular weights. They also found that the reaction between stannous octoate and alcohol substances could produce stannous alkoxide, which could initiate the ROP reaction by coordinately inserting into polymer chains. This initiation mechanism of the ring-opening reaction is known as the alkoxide initiation mechanism. The use of an alcohol substance with stannous octoate could significantly affect the ROP reaction through various reaction stages such as the formation of initiators, the transferring of chains, and also transesterification reaction. On the other hand, the application of carboxylic acid substances with stannous octoate catalyst could influence the ROP reaction through a deactivation reaction. Zhang et al. (1994) also found that the use of alcohol and carboxylic acid substances in ROP with stannous octoate significantly reduced the final molecular weight of the polylactide produced. However, the use of alcohol substances in a stannous octoate-catalyzed ROP reaction induced the rate of production of polylactide. In a study by Kowalski et al. (2000), they produced polylactide through an alkoxide initiation mechanism using ROP of L,L-lactide with stannous octoate as the catalyst and butyl alcohol (BuOH) as the coinitiator. They conducted the ROP of L,L-lactide at temperature lower than 100
C in tetrahydrofuran (THF) and the stannous octoate was initially reacted with BuOH by forming polymer chains with Oct-Sn-O end groups such as OctSnOBu, and OctSnOSnOBu compounds. These compounds acted as an actual initiator for the ROP of L,L-lactide. The findings of Zhang et al. (1994) and Kowalski et al. (2000) also found that the presence of an alcohol substance as a coinitiator in ROP of lactide with stannous octoate as catalyst induced the rate of polymerization of L,L-lactide to form polylactide in comparison to the presence of water traces, as summarized in Table 2.11. According to Yu et al. (2009) and

Table 2.11 Effect of Different Types of Coinitiator Used in Ring-Opening Lactide Polymerization With Stannous Octoate as the Catalyst on Types and Molecular Weights of Polylactides Formed and Reactivity of Polymerization

Coinitiator

Types of polylactides formed

Reactivity of polymerization

Molecular weight and polymerization time

References

Water traces

Linear polylactides

Lowest activity

Low molecular weight

Yu et al. (2009)

Higher than polyalcohols and water traces

Increase molecular weight and polymerization rate

Yu et al. (2009) Karidi et al. (2015) Averianov et al. (2017)

Increase molecular weight and molecular weight; however, longer polymerization time could decrease molecular weight due to faster degradation kinetics than linear polylactides due to higher cleavage rate of labile bonds along the polymer backbone

Kowalski et al. (2000) Korhonen et al. (2001)

Mono- and Bifunctional Alcohol • 1-Dodecanol • 1,4-Butanediol • 2-Hydroxyethyl methacrylate

Linear polylactides

Polyalcohols • Butyl alcohol • Pentaerythritol • 2,2-Hydroxymethyl-1, 3-propanediol • Di(trimethylolpropane) or DTMP • Glycerol • Linear polyglycidol (with 25 hydroxyl groups)

Higher than water traces but Branched polylactides lower than mono- and bi Four-arm polylactides functional groups. Four or six long branched Relative reactivity of hydroxyl chains groups decrease with Multiarm star branched increasing number of polylactides hydroxyl groups

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Averianov et al. (2017), the selection of different types of alcohol substances such as mono-, bifunctional hydroxyl alcohol, or polyalcohols (.2 hydroxyl groups) significantly affected the molecular structures of polylactides produced through the ROP of lactide with stannous octoate as catalyst, as summarized in Table 2.11. By referring to Table 2.11, the use of mono-, bifunctional alcohol substances such as 1-dodecanol and 1,4-butandiol as coinitiator or cocatalyst led to the synthesis of linear polylactides. The application of mono-, bihydroxyl group alcohol substances was also found to induce the reactivity of polymerization higher than water traces and polyalcohol substances (Yu et al., 2009). On the other hand, the branched polylactides could be synthesized by using polyalcohols such as butyl alcohol, pentaerythritol, as cocatalyst during the ROP of lactides (as shown in Table 2.11). According to researches conducted by Korhonen et al. (2001) and Karidi et al. (2015), polyalcohols such as pentaerythirol, di(trimethylolpropane) (DTMP), glycerol, and polyglycidol with 25 hydroxyl groups produced multiarm and four or six long-chain branched polylactides. They also claimed that the relative reactivity of hydroxyl groups of alcohol substances used was significantly decreased with increasing numbers of hydroxyl groups. In addition, they also found that the longer polymerization time of stannous octoate catalyzed ROP of lactides using polyalcohols as cocatalyst, which could significantly reduce the molecular weight of obtained polylactides due to the faster degradation kinetics of branched polylactides than linear polylactides. This is attributable to the higher rate of cleavage in the labile bonds along the polymer backbone of branched polylactides which degraded the obtained polylactide polymer (Karidi et el., 2015). Numerous researches have been conducted to synthesize new catalysts for the ROP of lactides to produce polylactides with higher conversion and molecular weight, as summarized in Tables 2.12 and 2.13. Routaray et al. (2015) successfully synthesized copper (II) complex supported by ONNO tetradentate ligand N,N’-bis(2-hydroxy-3methaxybenzaldehyde)-benzene-1,2-diamine (Cu-HMBBD) as catalyst for the ROP of lactides to form polylactides. They also further investigated the different types of coinitiator such as benzyl alcohol (BnOH), CH2Cl2, toluene, and THF on ROP of lactides with Cu-HMBBD as catalyst. The application of BnOH as coinitiator, together with Cu-HMBBD as catalyst, achieved optimum conversion up to 94.6% and also the highest molecular weight of the final product at up to 28,600 Da. Furthermore, the use of BnOH as coinitiator also reduced the polymerization time from 24 to 11 hours, which is attributed to the

Table 2.12 Effect of Different Types of Synthesized Catalysts on Molecular Weight and Conversion in Ring-Opening Polymerization of Lactides (Part 1)

Catalyst

Synthesis Process

Coinitiator

Copper (II) complex supported by ONNO tetradentate ligand N,N0 -bis(2-hydroxy-3methoxybenzaldehyde)benzene1,2-diamine (Cu-HMBBD)

Synthesized from 2-hydroxy-3methoxybenzaldehyde, 1,2-diaminobenzene and copper salts

Benzyl alcohol (BnOH) (polar) CH2Cl2 (polar) Toluene (nonpolar) Tetrahydrofuran (nonpolar)

Dimerix iron (III) complexes bearing Synthesized from condensation  acetylacetonate (acac) ligands reactions Fe(acac)3 to ethanol solution of SaiBuH Tridentate chiral Schiff base ligands Synthesized by adding Fe(acac)3  to an ethanol of SaiH Aluminum complexes: [2-(anilino)tropone]AlMe2 Aluminum complexes: {2-[2-(phenoxyl)anilino]tropone} AlMe2 Aluminum complexes: {2-[2-(2,6-di-isopropylphenoxyl) anilino]tropone}AlMe2 Aluminum complexes: {2-[2-(phenoxyl)aniline]tropone} AlMe2

Molecular Weight (Mw)/Conversion

References

Mw up to 28,600 Da; conversion: 94.6% Mw up to 22,900 Da; conversion: 92.4% Mw up to 19,400 Da; conversion: 80.7% Mw up to 17,100 Da; conversion: 56.5% Mw increase from 2200 to 2400 Da; conversion increase from 20% to 47% Mw increase from 2400 to 7300 Da; conversion increase from 22% to 97% Mw 5 14,100 Da; conversion: 92% Mw 5 14,100 Da; conversion: 92%

Routaray et al. (2015)

Kang et al. (2015) Kang et al. (2015)

Synthesis by using 2-(aniline) tropone and AlMe3 Synthesis using 2-[2-(phenoxyl) aniline]tropone and AlMe2

Benzyl alcohol (BnOH)

Synthesis using 2-[2-(2,6-diisopropylphenoxyl) anilino] tropone and AlMe2 Synthesis using {2-[2(phenylthio)aniline]tropone} and AlMe2

Benzyl alcohol (BnOH)

Mw 5 7340 Da; conversion: 80%

Li et al. (2015)

Benzyl alcohol (BnOH)

Mw 5 12,100 Da; conversion: 70%

Li et al. (2015)

Benzyl alcohol (BnOH)

Li et al. (2015) Li et al. (2015)

Table 2.13 Effect of Different Types of Synthesized Catalysts on Molecular Weight and Conversion in Ring-Opening Polymerization of Lactides (Part 2)

Catalyst

Synthesis Process

Synthesized from Zn(NO3)2  6H2O, • ZnDABCO 1,4-diazabicyclo[2,2,2]octane • CoDABCO (or known as H2BDC) and • NiDABCO • CuDABCO 1,4-benzenedicarboylate (DABCO) Metal organic frameworks (MOFs) MDABCO or M (where M 5 Co, Ni, Cu, Zn) Synthesized from ZnEt2 and proligands Zinc bis-pyrrolide-imine complexes: 2-(C4H4N-20 -CH 5 N)Ph-2-OPh 0 [bis{2-(C4H3N-2 -CH 5 N)Ph2-OPh}Zn] or Zn1 Synthesized from ZnEt2 and proligands Zinc bis-pyrrolide-imine complexes: 2-(C4H3N-20 -CH 5 N)C2H4O-Ph 0 [bis{2-(C4H3N-2 -CH 5 N) C2H4O-Ph}Zn] or Zn2

Coinitiator

Molecular Weight (Mw)/Conversion

References



• • • •

Benzyl alcohol (BnOH)

Mw 5 10,620 Da; conversion: .99% (temperature: 80
C; time: 96 h) Mw 5 9600 Da; conversion: 69% (temperature: 130
C; time: 1 h) Mw 5 13,040 Da; conversion: 97% (temperature: 80
C; time: 96 h) Mw 5 19,390 Da; conversion: 94% (temperature: 130
C; time: 1 h)

BnOH

Mw 5 4741 Da; conversion: Mw 5 4155 Da; conversion: Mw 5 2314 Da; conversion: Mw 5 2379 Da; conversion:

96% 95% 96% 90%

Routaray et al. (2015)

Caovilla et al. (2018) Caovilla et al. (2018)

Table 2.13 Effect of Different Types of Synthesized Catalysts on Molecular Weight and Conversion in Ring-Opening Polymerization of Lactides (Part 2)—cont’d

Catalyst

Synthesis Process

Synthesized from ZnEt2 and proligands Zinc bis-pyrrolide-imine 2-(C4H3N-20 -CH 5 N)C2H2Ph-2-OMe complexes: [bis{2-(C4H3N-20 -CH 5 N) C2H2Ph-2-OMe}Zn] or Zn3 Synthesized from ZnEt2 and proligands Zinc bis-pyrrolide-imine complexes: 2-(C4H3N-20 -CH 5 N)Ph-2-SPh [bis{2-(C4H3N-20 -CH 5 N)Ph2-SPh}Zn] or Zn4

Coinitiator

Molecular Weight (Mw)/Conversion

References

BnOH

Mw 5 9750 Da; conversion: 92% (temperature: 80
C; time: 96 h) Mw 5 19,330 Da; conversion 5 97% (temperature: 130
C; time: 1 h)

Caovilla et al. (2018)

BnOH

Mw 5 9600 Da; conversion: 96% (temperature: 80
C; time: 96 h) Mw 5 9660 Da; conversion: 70% (temperature: 130
C; time: 1 h)

Caovilla et al. (2018)

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good interaction between the polar solvent of BnOH and Cu-HMBBD during the polymerization reaction. Kang et al. (2015) also synthesized two types of iron complex compounds, which are dimeric iron (III) complexes bearing acetylacetonate (acac) ligands and tridentate chiral Schiff base ligands as catalyst for ROP of lactides to form polylactides. The application of tridentate chiral Schiff base ligands as catalyst in the ROP process of lactides was observed to provide a higher increment in the conversion from 22% to 97% and molecular weight of the final product from 2400 Da to 7300 Da when compared to dimeric iron (III) complexes bearing acetylacetonate (acac) ligands, as summarized in Table 2.12. Li et al. (2015) synthesized four different aluminum complexes, which were [2-(aniline)tropone]AlMe2, {2-[2-(phenoxyl)aniline]tropone}AlMe2, {2-[2-(2,6-di-isopropylphenoxyl)aniline]tropone} AlMe2, and {2-[2-(phenylthio) aniline]tropone}AlMe2. The ROP of lactides was conducted in toluene at a temperature of 80
C with benzyl alcohol as the coinitiator by using the synthesized aluminum complexes as catalyst. From their work, the use of [2-(aniline)tropone]AlMe2 as catalyst in the polymerization reaction was observed to provide the lowest conversion of 52%, while the application of {2-[2-(phenoxyl)anilino]tropone}AlMe2 as catalyst was found to provide the highest conversion and molecular weight (92% and 14,100 Da, respectively) in comparison to other aluminum complexes. Schmitz et al. (2018) also synthesized seven aluminum ion-pair complexes by reacting NNO Schiff base ketoimines with different substituents of tris(2,6-dimethylphenoxy) that act as catalyst for ROP of L-lactide and racemic-lactide to produce polylactides. Luo et al. (2017) synthesized four different types of metal organic frameworks MDABCO (for example: ZnDABCO) by using Zn(NO3)2  6H2O, 1,4-diazabicyclo[2,2,2]octane (H2BDC), and 1,4-benzenedicarboxylate (DABCO). MDABCO catalysts have been proved by Luo et al. (2017) to be highly active in ROP of L-lactides without a coinitiator to produce polylactides, especially ZnDABCO which showed the highest conversion and molecular weight as tabulated in Table 2.13. They further investigated the effect of ZnDABCO as catalyst on ROP of L-lactides with LA as the coinitiator. The application of LA as a coinitiator together with ZnDABCO as catalyst was found to greatly enhance the polymerization activity system. Caovilla et al. (2018) successfully synthesized four different types of zinc bis-pyrrolide-imine complexes by reacting ZnEt2 and different types of pyrrole-imine ligands. They investigated the effect of these synthesized zinc bis-pyrrolide-imine complexes as catalyst on conversion of lactides and the molecular weight of the final product during ROP of lactides. They found that the conversion of lactides achieved

92

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.99% when the Zn1 was used as catalyst in ROP of lactides in the presence of BnOH for polymerization temperature and time of up to 80
C and 96 hours. However, the lactides conversion was observed to significantly reduce when the polymerization temperature increased from 80
C to 130
C for a 1-hour duration. Among all synthesized zinc bis-pyrrolide-imine complexes (Zn1, Zn2, Zn3, and Zn4), the application of Zn2 and Zn3 as catalyst in ROP of lactides with BnOH as the coinitiator at a polymerization temperature and time of 130
C and 1 hours was found to achieve the highest molecular weight of up to 19,33019,390 Da and a conversion rate of 94%97%. Caovilla et al. (2018) also found that the Zn1, Zn2, Zn3, and Zn4 catalyzed ROP reaction of lactides to produce polylactides was faster in polymerization and better controlled when excess benzyl alcohol was used as the coinitiator.

2.5 Conclusion PLA is produced from the starting substance, LA, which is derived through the fermentation of carbohydrate. The production of PLA can be conducted by DP or ring-opening lactide polymerization methods. Of the two, ring-opening lactide polymerization remains the most widely used method, because this process has a higher yield and low toxicity. In addition, ring-opening lactide polymerization is suitable for lactide copolymerization with caprolactone, glycolide, or dioxanone. The traces of lactide and D-lactic acid present in the PLA are determined to avoid overdosing. The selection of catalyst can also be very important for both polymerization methods (either DP or ROP of lactides). A suitable catalyst can efficiently induce the conversion of LA or lactides into PLA and also increase the molecular weight of the PLA formed. Overall, understanding of the production and quality control of PLA are very helpful to ensure the feasibility of PLA in the long term.

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Further Reading Bezwada, R.S., Cooper, K., 1997. High strength, melt processable, lactide-rich, poly(lactide-co-p-dioxanone) copolymers. U.S. Patent 5 639 851, U.S. Patent Office.