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High molar mass poly(lactic acid) (PLA) is obtained by either the polycondensation of lactic acid or ring‐opening polymerization (ROP) of the cyclic dimer 2,6‐dimethyl‐1,4‐dioxane‐2,5‐dione, commonly referred to as dilactide or lactide (LA). The stereochemistry of LA plays a crucial role in dictating the properties of the polymers which have already been described in earlier chapters (Chapters 1 and 3).

L‐Lactide (LLA) is prepared with relatively high enantiopurity from corn starch fermentation, which polymerized to form poly(L‐lactide) (PLLA). PLLA is a versatile, semicrystalline, degradable polymer with a relatively high melting (T _m) and glass transition temperature (T _g). PLLA has mechanical properties which makes it interesting for many applications such as degradable plastic for disposable consumer products [1–3]. It is also of interest in medical applications [4], due to its favorable interactions with the cells. PLLA is also explored as a degradable scaffold where the transplanted cells could remold their intrinsic tissue superstructural organization, and thereby led to the desirable three‐dimensional structure and physiological functionality of a regenerated organ [5]. However, certain shortcomings of PLLA may need to be overcome to extend its applications. In particular, high crystallinity [6], brittle behavior with a very‐low elongation at break value, and the hydrophobic nature of the polymer demands a long degradation time. The properties of PLLA are tailored by copolymerization (random, block, and graft), change in molecular architecture (hyperbranched polymers, star shaped, or dendrimers), introduction of polar groups such as carboxyl, amino, or thiol‐based via end group or main‐chain functionalization, or blending with other polymers. Physical properties, such as T _g, T _m, crystallinity, hydrophobicity, and mechanical properties are significantly affected by such modifications. Furthermore, functionalization of PLLA can provide specific bio‐interactions with cells, which is specifically needed in tissue engineering. Several reviews have summarized how functionalization of lactide and copolymerization with other hydroxyl‐acid‐based monomers influence the properties and applications of the resultant copolymers [5,7–15]. In this chapter, preparation of polymers and copolymers of LAs with different structures, using polycondensation and ROP, is described. The influence of macromolecular structure and composition on the properties of structurally modified polymers is also discussed. The stereocopolymers of LA prepared by the polymerization of various stereoisomers are discussed in a subsequent section in this book and will not be discussed here.

Typical comonomers and polymers which are used for lactic acid or LA copolymerization include glycolic acid or glycolide (GA) [16–22], poly(ethylene glycol) (PEG) or poly(ethylene oxide) (PEO) [17, 18, 21,23–42], poly(propylene oxide) (PPO) [43, 44], β‐butyrolactone (BL) [45–48], δ‐valerolactone (VL) [49, 50], ε‐caprolactone (CL) [22,51–58], 1,5‐dioxepan‐2‐one (DXO) [59–64], p‐dioxanone [65–70], trimethylene carbonate (TMC) [58, 71], and N‐isopropylacrylamide (NIPAAm) [41,72–74]. The structures of some of these comonomers are given in Figure 4.1 [22, 42]. Monomer distribution (random or block) in the copolymers depends on the reactivity of monomer pairs, nature of the catalysts, and polymerization conditions.

FIGURE 4.1 Structures explored as comonomers with lactide monomer. (a) GA, (b) flourine substituted lactide monomer, (c) CL, (d) hydroxyl functionalized CL, (e) p‐dioxanone, (f) DXO, (g) BL, (h) VL, (i) TMC, (j) hydroxyl functionalized cyclic carbonate derivatives.

FIGURE 4.2 Structures of catalysts used in lactide polymerization.

Various catalysts and initiators used for ROP of LA monomers/comonomers are shown in Figure 4.2. Organometallic compounds such as stannous octoate Sn(Oct)₂, aluminum isopropoxide [75], and zinc salt [76] as oxides, carboxylates, and alkoxides are reported as effective catalysts/initiators for polymerization reaction. Among all catalysts, Sn(Oct)₂ is usually preferred as it mediates ROP reaction at a faster rate. However, resultant polymer showed a lower molar mass than when reaction was catalyzed by zinc metal or zinc lactate [13, 77]. Sn(Oct)₂ allows formation of atactic PLAs with well controlled architecture, linear and star shape, and that too with high efficiency. Despite the usage of high temperature (usually 140°C) and/or high pressure, Sn(Oct)₂ allows low percentage racemization [78]. Zn‐catalyzed PLA exhibited higher hydrophilicity and degradation susceptibility than the Sn‐mediated polymerization [19]. A partial esterification of alcohol chain ends in PLA by an octanoyl group is reported in Sn(Oct)₂ catalyzed polymerization reaction [79]. While in case of Zn, occurrence of an extra lactoyl group is likely observed [80].

Metallic salts can either be used alone or along with a co‐initiator (water or alcohol) to affect polymerization of LA. Presence of co‐initiators mainly alcohols allowed formation of different molecular architecture and controlled growth of both the pristine and copolymers based on PLA. They form the cores, thus allows a different architectural growth of polymer in space. It is considered as an effective synthetic approach to tune the macromolecular structure of PLLA and thus the resultant polymer showed significantly different physical properties than that obtained otherwise. Linear to branched to star‐shaped [81] polyol co‐initiators utilized in LA polymerization are shown in Figure 4.3.

FIGURE 4.3 Polyol cores used for synthesis of different architecture in lactide‐based copolymers/polymers.

There are many examples of biocompatible and FDA‐approved (Food and Drug Administration) medical devices, which contain polymers composed of LA with or without other comonomers. They may find utility in various commercial products ranging from surgical sutures, tissue engineering scaffolds to drug delivery systems [82]. Normally, Sn(Oct)₂ is used as catalyst during the polymerization, but utility of zinc lactate is also reported [13, 19, 77]. A Sn residue of 306 ppm is detected in PLA [77]. Sn(Oct)₂ itself has been found to be slightly cytotoxic, and it is reported that Sn(Oct)₂ is considered harmful at a dietary level of 0.1% [18, 83]. When polymerization reaction is pursued using high catalyst to monomer ratios, residues such as ethyl‐2‐hexanoic acid or hydroxy tin octanoate or tin oxide [79] are detected. However, such impurities can alternatively be removed by repeated dissolution and precipitation of polymer and/or in combination with other purification techniques. With the raising environmental and health concerns and knowing traces of metal‐related toxicity in polymers, organo‐ or enzymatic‐catalyzed polymerization reactions appeared as a safe and attractive alternative to metal‐catalyzed systems. Organo‐ and enzymatic catalysis are comparatively nontoxic, mild, and eco‐friendly in nature [84–86]. Unlike usual metallic catalysts (Sn, Zn, Ti, etc.), organocatalysts containing non‐oxophilic moieties allow their easier removal, especially during the synthesis of oxygen‐atom‐rich polymers [87]. In general, organic catalysts being miscible within the monomer may allow a better control in polymerization conditions and thus provide avenues to modulate the copolymer composition. For example, combination of organocatalyst such as Brønsted acid (DPP, diphenylphosphate) and Brønsted base (DBU, 8‐diazabicyclo[5.4.0]undec‐7‐ene) assist ROP of different type of monomers in one pot to form sequence controlled multiblock copolymers such as poly(VL‐b‐LA) and poly(VL‐b‐TMC‐b‐LA), which otherwise could not be realized in a single pot using either DPP or DBU as a catalyst [88].