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 sequence is embedded into a large cyclic macromonomer containing a reactive unit that can be systematically cleaved. Upon cleavage, the opened rings join with other units in a controlled manner to form long chains that incorporate sequenced units. Advantages offered by this methodology for formation of copolymers involves no dependence on the chemical behavior of the constituent monomers during polymerization reaction, easy scalability with a high degree of molecular weight control, and copolymers thus formed showed low dispersity. Selectivity‐enhanced entropy‐driven ring‐opening metathesis polymerization (SEED‐ROMP) of large, strain‐free, ring‐chain macromonomer with double bond as reactive unit form linear polymeric chains with specific sequence of monomer units. A cis‐ vs trans‐double bond in macromonomer found to polymerize faster using a cis‐selective Grubbs’ catalyst in 10 min vs 2 h with similar conversion. Thus, current methodology offers a good synthetic control in designing well‐defined controlled architecture for monomer arrangement in the polymers.
Abe and Tabata [242] demonstrated thermal properties and crystalline structures for a class of periodic aliphatic polyesters, with 3‐hydroxybutyrate and lactate units, can be varied over a wide range of temperatures based on stereosequence manipulations. Similarly, a statistical variation in chain microstructure found to affect various hydrolytic degradation rates in poly(lactide‐co‐ε‐caprolactone) matrices [243].
Besides modification in synthetic strategy, a variation in catalyst design is also exploited. Organocatalysts such as phosphazene‐based catalysts reported to form alternating PLGA with high regioselectivity and low dispersity [239]. Likewise, lactide‐based polymers, the nature of SC formation differs significantly between pure enantiomeric alternating copolymers to enantiomeric alternating LA‐based copolymers, poly(LLA‐alt‐GA)/poly(DLA‐alt‐GA) blends, as supported by WAXD and DSC [244].
4.5 PROPERTIES OF LACTIDE‐BASED COPOLYMERS
The physical properties and degradability of PLA copolymers can be easily controlled by changes in the polymer architecture by altering the structure of monomers and feed ratio to affect the composition of the repeat units, flexibility of the chain, inclusion of labile linkages, molar mass, crystallinity, and orientation of the backbone chains. Tong summarized the T g and T m of various aliphatic polyesters depending upon the tacticity and functionality present in the polymer [245]. Properties of PLA depend on the stereoisomers used for their preparation. PLLA and PDLA are semicrystalline hard materials with modulus of 2.7 GPa, tensile strength of 50–70 MPa, elongation at break of 4%, flexural modulus of 5 GPa, and flexural strength of 100 MPa [246–249]. The T m is around 180°C and T g is 60–65°C. The molar mass of the polymer, as well as degree of crystallinity, showed a significant influence on the mechanical properties [250–254]. Polymerization of a racemic mixture of 1 : 1 D,D‐LA and L,L‐LA or meso‐LA gave an amorphous polymer with a T g of 55–60°C and a tensile modulus of 1.9 GPa. The in vitro degradation of PLLA is much slower than PMLA (M = meso) due to its crystalline nature, and it takes two years for complete degradation of the former polymer. Surprisingly, a high crystallinity in the rac‐PLA is observed when polymerization of a racemic monomer in the presence of a racemic catalyst, a chiral Schiff’s base complex of aluminum was carried out [255]. This stereoselective mode of polymerization is accounted to the formation of stereocomplex as supported by powder X‐ray diffraction and NMR studies. Ovitt and Coates reported the formation of isotactic stereoblock PLA where each enantiomerically pure block contained an average of 11 LA units. The polymer showed
