A novel degradable chestnut‐shaped polymer having a PLA shell and hyperbranched D‐mannan (HBM) was synthesized by polymerization of LLA and HBM with DMAP as catalyst. The number of PLA chains on PLA–HBM could be controlled by the ratio of DMAP to sugar [195].
Hyperbranched vs linear polymer structures based on Sn(Oct)2‐mediated one‐pot copolymerization of glycidol and LA can be achieved by controlling the reaction temperature. Usage of different temperature conditions allowed a controlled occurrence of epoxide ring opening that leads to hyperbranching. Epoxide ring opening was prevented in low‐temperature solution polymerizations, resulted in essentially linear PLA functionalized with an epoxide end‐groups [196].
LA has been polymerized in a star‐shape to poly(amidoamine) dendrimer (PAMAM), the copolymer was synthesized by bulk polymerization of LA with PAMAM. Unlike the linear PLA with similar molar mass, PAMAM‐g‐PLA revealed a higher hydrophilicity and a faster degradation rate. The highly branched structure significantly accelerated the release of water‐soluble bovine serum albumin from these graft copolymers, whereas a time lag was observed in linear PLLA of similar molar mass [197].
4.4.3 Periodic Copolymers
Periodic lactide copolymers have garnered significant interest over a period of years and recently emerged as one of the upcoming strategy to affect polymer properties [90198–244]. Alternating copolymer is a subset of periodic copolymer. These copolymers hold special relevance as they offer good microstructure control by sequential arrangement of monomer with retention of their stereochemistry in polymer, as compared with random copolymers. Both step growth and chain growth polymerization have been used for the synthesis of periodic copolymers as shown in Figure 4.18.
Tsuji et al. [203] successfully synthesized s‐PLA by adopting the procedure reported by Stayshich and Meyer [90, 204]. Usually s‐rich PLA form amorphous polymers due to insufficient syndiotactity or crystallization, as determined by wide‐angle X‐ray diffractometry (WAXD). On the contrary, h‐/i‐rich (isotactic‐rich) PLA showed existence of transient aggregate regions, stereocomplex (SC), which are believed to form due to enhanced interactions between L‐ and D‐lactoyl unit sequences [205] in PLLA and PDLA. The occurrence of such domains is supported by crystalline infrared, terahertz (THz) vibrational spectroscopy, and crystal orbital density functional theory [206, 207]. SC formation of PLLA and PDLA as homopolymers and random copolymers is gaining significant attention. Interestingly, upon SC formation between PLLA and PDLA homopolymers and their copolymers, the resultant polymers showed an improved mechanical performance, resistance to hydrolytic degradation, and a higher thermal stability [208–215]. Thus, SC formation is advantageous feature as it presents opportunities for advancement in scope of polylactide chemistry [208–219]. For example, an increase in elastic modulus to 20 from 14 GPa of the PLLA/PDLA as SC vs homo‐crystalline region, respectively, is achieved [220]. The origin of this substantial change is accounted to the strong interchain interactions between PLLA and PDLA. A high degree of SC formation is further noticed by incorporating additional structure motifs, which extends hydrogen bonding interactions between the polymer chains [221]. Even variation in catalyst assists in situ SC formation during monomer polymerization. For example, DL‐lactide polymerization performed using achiral iron complexes as catalyst at ambient temperature resulted in SC formation [222]. Seemingly SC formation presents opportunities for advancement in scope of polylactide chemistry [208–219]. These favorable interactions offer a multitude in variation in resultant polymer properties, which are further guided by the variation in type, concentration, and sequence of monomer units in the polymer architecture [209, 210, 214,223–228]. A retention of symmetry between PLLA and PDLA in the crystal lattice [206, 229], with a wide percentage variation in PLLA fractions (30–70%) is observed [207, 230].
FIGURE 4.18 Common routes to synthesize random and alternating PLGA and typical synthesis of stereo‐ and regio‐selective ROP using (SalBinam)AlOR catalyst [199].
Another approach for SC formation is observed by blending of enantiomeric PLLA and PDLA or upon synthesis of stereoblock copolymers with enantiomeric PLLA and PDLA blocks [208–215]. Besides homopolymers, binary and tertiary system containing PLLA and PDLA are also reported. Formation of such crystalline lattice formation in enantiomeric random, staggered random, and enantiomeric alternating copolymer blends of LLA or DLA with hydroxyalkanoic acids is supported by WAXD. Notably, in these repeating units, only one type of chiral center from lactic acid units existed. Recently, SC formation between enantiomeric alternating copolymers consisting of repeating units with two types of chiral centers, D,D‐configured poly(DLA‐alt‐D‐3‐hydroxybutanoic acid) and L,D‐configured poly(LLA‐alt‐D‐3‐hydroxybutanoic acid), is also reported [231]. A significant variation in the T m between the two polymers (233 vs 83°C) is observed. A very high value of the T m of SC crystal (~230°C) is observed, which is among the highest value reported in the aliphatic polyesters including poly(glycolate) [40].
Among other lactide copolymers, PLGA has garnered significant interest due to its nontoxic hydrolytic degradation pathway in vivo, with tunable degradation rates and T g value lies just above human body temperature for a random arrangement of units [232]. When PLGA is used for drug delivery application, the arrangement of GA and LA units are of paramount importance as they govern the degradation rates to affect a sustained drug release profile [233]. A slow but controlled polymer degradation property of copolymers renders them ideal candidates for the investigation to study the role of sequential arrangement of monomers. Alternating sequence copolymers of PLGA tend to degrade at slower but at a constant rate [234], thus allowing a sustained release of encapsulated guests, as compared to a random copolymer. Synthetic approaches adopted to affect arrangement of GA and LA units in polymer are shown in Figure 4.18. Usually, PLGA is synthesized by the ring‐opening polymerization (ROP) of LA and GA, yielding a random copolymer [235]. In step‐growth segmer assembly polymerization (SAP) produces PLGA with a repeating sequence that depends on the preformed oligomer used [90]. Repeating sequence copolymers (RSCs) with complex microarchitecture from lactic acid (LA) and glycolic acid (GA) such as poly(LA–GA), poly(GA–LA–GA), poly(LA–LA–GA), as syndiotactic, and isotactic were prepared by segmer assembly polymerization (SAP) approach [90]. End‐groups of PLGA copolymers containing exact sequenced segmers, i.e., monodisperse units (2–8 monomer units) were further utilized for subsequent condensation polymerization by Li et al. [236]. The SAP approach is a laborious and multistep process. It is a direct polycondensation and produce alternating PLGA reliably but face challenges in controlling molecular weight and Đ lies between 1.3 and 2. A 10 times higher rate of GA incorporation than LA is observed, which is attributed to the steric effect of the methyl substitution [237]. ROP of 3‐methyl glycolide (MeG) has also been used to prepare alternating PLGA, with varying degrees of sequence [238, 239]. Alternating PLGA with a very high regioselectivity of 98% is achieved with (S)‐MeG with a chirality‐directed regioselective approach [240], for the sequence‐controlled synthesis of PLGA as illustrated in Figure 4.18.
Meyer et al. [241] reported selectivity enhanced entropy‐driven ring‐opening metathesis polymerization (SEED‐ROMP) for the preparation of copolymers with repeating sequences. In this strategy, a preformed