Poly(lactic acid). Группа авторов

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].

4.2 COMONOMERS WITH LACTIC ACID/LACTIDE

      4.2.1 Glycolic Acid/Glycolide

      The polymerization of LA and GA can proceed by anionic, carbocationic, or coordination insertion mechanisms and is well described in the previous sections. Poly(lactic acid‐co‐glycolic acid) [poly(LA‐co‐GA) or PLGA] of varying molar masses and compositions are also available commercially.

Low molar mass PLGA, copolymers were prepared by the step‐growth polycondensation of lactic acid and glycolic acid. Such copolymers are obtained by polycondensation reaction of the desired composition of monomers in the presence of heat. The reaction is favored in forward direction by removal of evolved water by distillation at atmospheric pressure or under vacuum conditions. The copolymers thus obtained are either brittle and glassy or waxy and sticky, depending on the feed composition and the resultant molar mass of the polymer. A copolymer with a weight‐average molar mass of ≥15,000 g/mol was prepared by dehydration condensation of lactic acid and glycolic acid in diphenyl ether in the presence of tin powder [89].

      On the other hand, high molar mass copolymers are prepared by ROP of LLA or DLA and 1,4‐dioxane‐2,5‐dione or GA under inert atmosphere or in vacuum. The polymerization can be carried out in bulk, solution (tetrahydrofuran (THF), toluene, dioxane, etc.), or suspension or emulsion conditions. The temperature of bulk polymerization is generally in the range of 100–160°C, whereas in solution polymerization, low temperature (0–25°C) was used to minimize the side reactions (inter‐ and intra‐molecular transesterifications). PLGA copolymers having lactoyl content of 70–90% were prepared by copolymerization at 160°C for 20 h using a desired ratio of monomers and Sn(Oct)₂ as a catalyst [21]. The weight‐average molar mass of the copolymers ranged from 9.07 to 7.95 × 10⁴ g/mol. Bulk polymerization of LLA and GA (75 : 25) using Sn(Oct)₂ at 60°C for 2 h (in vacuum to remove traces of water) and at 165°C for 4.5 h gave a polymer with weight‐average molar mass of 50,000–70,000 g/mol [18].

      Block copolymers of LA and GA have been synthesized by sequential addition of monomer onto the reactive chain end of polymer produced from another monomer and by using a hydroxyl‐terminated homopolymer as a chain transfer agent [17]. Even small differences in the sequence of monomer units in PLGAs can be easily noticed and determined by (¹H and ¹³C) NMR. Especially, the diastereotopic methylene resonances for the glycolic units of the copolymers are well noticed in the ¹H NMR. Thus, NMR technique is considered as sensitive and useful technique to provide a better structure–property correlation [90].

      4.2.2 Poly(Alkylene Glycol)

      The unique properties of PEG, such as solubility in water and polar organic solvents and its insolubility in nonpolar solvents such as ethyl ether and heptane, lack of toxicity, rapid clearance from the body [32], high mobility, and FDA approval of PEG based medical device or formulation for internal consumption, make it a suitable polymer for the preparation of block copolymers of LA or LA–GA. Copolymers of LLA with hydrophilic poly(ethylene oxide) and/or poly(propylene oxide) are vastly reported [25, 43, 44]. Several triblock copolymers of LLA, D,L‐lactide (DLLA), and PEO, with PEO as the central block are reported in the literature [24]. These copolymers are more hydrophilic, flexible, and revealed a higher tendency to degrade than PLLA homopolymer [40]. The hydrophilic domains generated by the EO‐based blocks act as surface modifier of hydrophobic LA‐based domains of the microspheres and thus promote the stability of water‐soluble molecules (e.g., λ‐DNA) with efficient loading within these microspheres. The degradability and biocompatibility of these copolymers make them suitable candidates for controlled delivery of water‐soluble molecules [39]. Diblock and triblock polymers were prepared by bulk or solution polymerization using stannous chloride [39], Sn(Oct)₂ [28, 35, 36], potassium tert‐butoxide [91], sodium hydride [29], calcium hydride/Zn [34], or zinc metal [38] as catalysts. Block copolymers were also prepared in the absence of added catalyst [31].

High polymerization temperatures generally reduce the molar mass of the PLLA [35]. A wide range of copolymers were prepared by varying the molar mass of PEG (1000–30,000 g/mol) and LLA/PEG ratio in the initial feed. A representative structure of such triblock copolymers is depicted in Figure 4.4. The resultant triblock copolymers showed phase separation, due to the hydrophobic and hydrophilic nature of the segments in the polymer backbone, as shown by differential scanning calorimetry (DSC) and wide‐angle X‐ray scattering analysis (WAXS) studies.

Synthesis and applications of copolymers obtained by adding LA to PEG is widely reported in the literature [92–96]. Transesterification reaction of PLA (M _w 5000–400,000 g/mol) with poly(alkylene ethers) (M _w 500–50,000 g/mol) having ≥1 OH per polymer unit was carried out under melt conditions in the presence of Ti(OBu)₄ as a catalyst at 200°C to obtain a high molar mass PLA copolymer. The obtained copolymer showed better flexibility, transparency than that obtained by ROP of lactide in the absence of the above‐mentioned polyalkylene glycol [97]. A synthetic strategy for the preparation of ABA triblock copolymers, consisting of poly(LLA‐co‐GA) and PEG synthesized under bulk conditions, is shown in Figure