Polyesters based on diacid monomers

Advanced Drug Delivery Reviews 55 (2003) 585–609www.elsevier.com/ locate/addr

P olyesters based on diacid monomers*U. Edlund, A.-C. Albertsson

Department of Polymer Technology, Royal Institute of Technology, SE-100 44 Stockholm, Sweden

Received 23 November 2002; accepted 30 January 2003

Abstract

Polymers with ester linkages in their main chain comprise a family of polymers with immense diversity and versatility.This review deals with the preparation of such polymers from dicarboxylic acid monomers, and the result in terms ofproperties and applicability. Polyesters alone, and their copolymers with amides, anhydrides, urethanes, imides, ethers orother functional groups, offer countless opportunities to tune the properties of the resulting material within a broad range. Ofparticular interest is the inherent biodegradability of the ester linkage. Biodegradability is sought after in a wide range ofapplications, above all in the preparation of environmentally friendly polymers and biomedical materials for temporarysurgical use and in drug delivery. 2003 Published by Elsevier Science B.V.

Keywords: Ester; Dicarboxylic; Diacid; Polycondensation; Polyester; Poly(ester–amide); Poly(ester–anhydride); Poly(ester–urethane);Poly(ester–imide); Poly(ether–ester); Degradation; Hydrolysis; Biomedical

Contents

1 . Polyesters: an introduction ....................................................................................................................................................... 5861 .1. Background ..................................................................................................................................................................... 5861 .2. Synthesis ......................................................................................................................................................................... 5861 .3. Degradation ..................................................................................................................................................................... 5881 .4. Potential in the field of drug delivery ................................................................................................................................. 589

2 . Polyesters based on diacid monomers ....................................................................................................................................... 5892 .1. Polyester fibers ................................................................................................................................................................ 5922 .2. Enzymatically derived polyesters ...................................................................................................................................... 593

3 . Poly(ester–amide)s .................................................................................................................................................................. 5934 . Poly(ester–imide)s................................................................................................................................................................... 5965 . Poly(ester–urethane)s .............................................................................................................................................................. 597

Abbreviations: AAc, adipic acid; BDO, 1,4-butanediol; FA, fumaric acid; IPA, isophthalic acid; LC, liquid crystalline; MDI,methylene-4,49-diphenyldiisocyanate; PA, phthalic acid; PCL, poly(´-caprolactone); PBS, poly(butylene succinate); PBT, poly(butyleneterephthalate); PEA, poly(ethylene adipate); PET, poly(ethylene terephthalate); PGA, poly(glycolic acid); PHA, poly(hydroxyalkanoic acid);PLA, polylactide; Poly(lactic acid); ROP, ring-opening polymerization; SA, sebacic acid; TDI, toluenediisocyanate; TPA, terephthalic acid

*Corresponding author.E-mail address: [email protected](A.-C. Albertsson).

0169-409X/03/$ – see front matter 2003 Published by Elsevier Science B.V.doi:10.1016/S0169-409X(03)00036-X

mailto:[email protected]

586 U. Edlund, A.-C. Albertsson / Advanced Drug Delivery Reviews 55 (2003) 585–609

6 . Poly(ester–anhydride)s ............................................................................................................................................................ 6007 . Poly(ether–ester)s.................................................................................................................................................................... 6028 . Miscellaneous polymers derived from diacid monomers............................................................................................................. 6039 . Future outlook......................................................................................................................................................................... 604References .................................................................................................................................................................................. 604

1 . Polyesters: an introduction in the 1930s, exploring polyester and polyanhydridesynthesis by polycondensation [1–3]. His work also

1 .1. Background provided the fundamentals for analysis of steppolymerization kinetics and set forth the Carothers’

The family of polyesters comprises all polymers equation, relating the degree of polymerization to thewith ester functional groups in the polymer back- extent of reaction:bone. The chemistry of the structural units connect-

1]ing the ester groups can be varied over an immensely ]]X 5 (1)n (12 p)broad range, making the polyesters a diverse groupcovering everything from labile biomedical matrices

Generally, polycondensation is a task more dif-to liquid crystals, fibers, and temperature resistantficult than chain polymerization, since high molecu-performance materials. Polyesters were historicallylar weights can only be achieved at very highthe first family of synthetic condensation polymersconversions (.98–99%). An exact stoichiometricand were investigated as part of Carothers’ pioneer-balance of monomers is of paramount importance ining studies on polymerization in the 1930s [1,2].this respect, and while this is readily achieved usingEsterification is thermodynamically a reversiblepurified AB-type monomers, it does present a practi-reaction. Hence, all polyesters are theoretically po-cal problem when using AA and BB type monomerstentially degradable in the presence of water thatsuch as diacids and diols. Also, the ester formationcauses cleavage of the main chain ester bonds. Inreaction is characterized by an equilibrium andpractice, the hydrophobicity of aromatic polyestercontinuous removal of the byproduct is necessary tobackbones effectively excludes water from the vic-drive the reaction toward higher conversion. Toinity of labile bonds and only aliphatic polyestersfurther facilitate high conversion, long reaction timeswith reasonably short methylene segments betweenand high temperatures are needed.the ester bonds will degrade over the time scale of

By using polyfunctional acid monomers, hyper-observation.branched, dendritic, star, and network polyesterswith different geometries can be prepared [4,5]. Such

1 .2. Synthesis polyesters find use in many fields, e.g pharmaceu-ticals, agrochemistry, adhesives and coatings,

Polyesters are typically synthesized by stepwise catalysts, cosmetics, inks and toners, lubricants, nanopolymerization of difunctional monomers of the AB devices, pharmaceuticals, selforganizing assemblies,type, i.e. hydroxy acids, or from a combination of thermoplastics and thermosets, and viscosity modi-AA and BB difunctional monomers [1,2]. Such fiers. However interesting these macromolecules maypolymerization reactions are commonly referred to as be, polyacid monomers do not fit the scope of thispolycondensation since they involve the formation of review and will henceforth not be addressed.a small byproduct, e.g. water. Polycondensation of A straightforward route to aliphatic polyesters isdifunctional monomers include the esterification of the ring-opening of cyclic lactones. Ring-openingdiacids and diols, diacid chlorides and diols, or the polymerization (ROP) holds many advantages com-ester interchange reaction of diesters and diols, as pared to traditional condensation polymerization andoutlined in Fig. 1. Network polyesters are formed is often the method of choice for the preparation offrom monomers with functionalities greater than two. high-molecular weight aliphatic homo- and copolyes-Carothers pioneered the studies of polycondensation ters. For instance, ROP works under milder con-

U. Edlund, A.-C. Albertsson / Advanced Drug Delivery Reviews 55 (2003) 585–609 587

Fig. 1. Preparation of polyesters by stepwise polycondensation.

ditions and shorter reaction times [6,7]. High conver- less, enzymatic polyesterification of diacid mono-sions can easily be reached without considerations of mers has also been reported as will be furtherremoval of reaction byproducts and the use of discussed in a later section [16–19].stoichiometric balance of monomers, features of Recently, an alternative polycondensation route togreat industrial importance. The ring-opening poly- polyesters has been proposed, involving the reactionmerization of lactones, investigations of mechanisms of silylated monomers [20].and initiators are extensively documented in litera- Macromers are shorter macromolecules or oligo-ture [6–13]. Ring-opening of cyclic polyanhydrides mers with functional groups in one or several chainin the presence of a catalyst represents another ends. The functional groups are subsequently used inconvenient one-pot synthesis route to polyesters coupling or polymerization reactions with other(Fig. 2). monomers or macromers affording segmented

Enzymatic polyesterification has been extensively macromolecules [21–26]. Depending on the chemis-studied [14] and has recently gained increasing try of the functional group(s), radical, ionic, coordi-attention. Enzymatic catalysis comes naturally when nation, condensation or ring-opening polymerizationdealing with polyesters of bacterial origin, such as techniques can be applied. Macromer technologythe poly(hydroxy alkanoate)s (PHA)s, or enzymati- opens up a world of possibilities. The macromercally degradable polyesters such as polylactic acid. functionality is not limited to two, star- or branchedHence, synthetic, enzyme-mediated, preparation of macromers are equally useful and by proper choicevarious PHAs has gained most attention and some of its structure and architecture, anything from linearprocesses are now commercialized [15]. Neverthe- block copolymers to advanced graft-, dendritic and

Fig. 2. Preparation of polyesters by ring-opening polymerization of (a) lactones, and (b) cyclic anhydrides.


ladder architectures can be prepared. This technology illustrated and exemplified by polylactic acid, PLA,also represents an effective method to combine in Fig. 3. Chain scission results in the formation ofhydrophobic to hydrophilic components [27]. A great carboxylic end-groups that, due to their acidic nature,variety of macromers has been reported as precursors will enhance the rate of further hydrolysis. Thisof graft- and block copolymers and macromer tech- mechanism is denoted ‘autocatalysis’ [35] and makesnology has become a standard route to interpenetrat- polyester matrices truly bulk eroding.ing networks. Macromers with carboxylic acid end The inherent degradability of aliphatic polyestersgroups show great potential as precursors for seg- makes them highly interesting for applications wheremented polyesters. Polyester macromers with other the environmental impact is a concern, e.g. packag-functional end groups, e.g. hydroxy ends, are im- ing, disposable items, and agricultural mulch films.portant in the preparation of polyester copolymers A limitation of the aliphatic polyesters in this respectsuch as poly(ester–urethane)s, poly(ester–amide)s, is their higher cost, compared to commodity vinyland poly(ester–anhydride)s. Such polymers will be plastics such as polyethylene. Blends of polyestersaddressed in later sections. and fillers have been presented to reduce the material

cost. These fillers are typically derived from abun-1 .3. Degradation dant natural materials such as starch [36] or wheat

gluten [37]. Poor compatibility between the filler andAs previously stated, all polyesters are inherently the polyester matrix is however an issue of concern,

degradable as they hold hydrolytically labile ester having a deteriorating influence on the mechanicalbonds in the main chain. In practice however, only properties of these materials. Degradable polyestersaliphatic polyesters with reasonably short methylene are also of great interest in biomedical applicationssegments between the ester bonds will degrade over where temporary aid is needed, typically sutures,a reasonable time scale. Such aliphatic polyesters bone pins, stents, scaffolds, and in drug deliverydegrade chemically by hydrolytic cleavage of the matrices. Polymers derived from aliphatic diacidbackbone ester bonds [28–30], by enzymatic promo- monomers are also interesting from an ecologicaltion [31,32], and in a biological environment often a point of view, as the search for ‘green polymers’combination of these two processes [33]. Microbial derived from renewable resources intensifies todegradation involves the action of excreted enzymes overcome the escalating waste disposal problems.such as lipases [34]. Hydrolysis is catalyzed by Aliphatic diacid monomers may be derived fromeither Brønstedt acids or bases and is schematically vegetable oils.

Fig. 3. Degradation of a polyester (polylactide) by hydrolytic scission of the main chain ester bonds.


1 .4. Potential in the field of drug delivery exceed 5000 [40]. In fact, a general problem con-nected with the esterification polycondensation pro-

Aliphatic polyesters are degradable, as are co- cess is the difficulty of preparing high molecularpolymers of esters with other hydrolyzable moieties weight products. Another limitation of the aliphaticsuch as anhydrides or carbonates. Thus, polymers polyesters is their general lack of structural regulari-with ester linkages in their main chain stand out as ty, which together with moderate molecular weightssuitable for a range of temporary biomedical applica- leads to materials with low degrees of crystallinity,tions, not in the least for drug delivery, since the limited strength and weak mechanical properties. Toneed for surgical removal of the depleted device is overcome these shortcomings, synthetic chain exten-eliminated. Suitable drug delivery candidates must sion has been suggested to achieve high molecularhowever not only be biodegradable but also fit the weights. Chain extension with adipoyl chloride ishigh prerequisites of biocompatibility. A suitable easily mediated through simple addition of the chaincandidate for biomedical applications should also extending agent to a solution of the preformedoffer processability, sterilizability and a reasonable polyester and a catalyst and subsequent reflux of theshelf life. The family of aliphatic polyesters has been solution for a few hours [41]. A similar chainby far the dominating choice for materials in degrad- extension methodology makes use ofa,v-bis-able drug delivery systems [38]. The most popular chloroformates derived from phosgene and diols asaliphatic polyesters for biomedical and drug delivery the chain extension agents [42]. Chain extension ofapplications, e.g. PLA, poly(´-caprolactone) (PCL), polyesters has also been afforded with diepoxidesand poly(glycolide–co-lactide) (PLGA), are typically [43] and diisocyanates [44].prepared by ring-opening polymerization from cyclic Aliphatic homo- and copolyesters prepared bymonomers. As this review is concerned with polyes- polycondensation of simple diols and diacids such asters based on diacid monomers, lactone based polyethylene glycol or 1,4-butanediol (BDO), and suc-mers will henceforth not be considered. cinic acid, or adipic acid (AAc) or similar monomers,

are biodegradable [33,41,45]. Such polyesters, typi-cally poly(butylene succinate) (PBS), and poly-

2 . Polyesters based on diacid monomers (butylene succinate–co-butylene adipate) are nowa-days commercially available under the trade name of

Polyesters can typically be formed by a stepwise Bionolle [46] from the Japanese company Showacondensation reaction from difunctional monomers High Polymers. To achieve sufficiently high molecu-such as diols and diacids [33]. The composition of lar weights, the polycondensation process involvesthe diacid can be varied perpetually allowing the chain extension of the ester oligomers by means ofstructure and properties of the resulting polyesters to diisocyanate coupling agents. The awareness of thespan over a very broad range [39]. Diacids that have environmental impact of polymers has drawn in-been used for preparation of polyesters are far too creasing attention to degradable materials, andplentiful to all being mentioned here. Nevertheless, Bionolle structure, properties, and degradation be-some structurally relatively simple diacids are of havior have been frequently reported in literaturesuperior importance for polyester production [46–52]. Bionolle is typically a semicrystalline ther-throughout industry and academia, as outlined in Fig. moplastic with good processability and flexibility4. and strength comparable to that of low-density

Carothers’ groundbreaking work in the field of polyethylene. Several grades of Bionolle are pro-polycondensation included a systematic study of the duced on an industrial scale since the early 1990s.reactions between aliphatic diols and diacids of Apart from synthetic chain extension, many othervarious lengths. The aim was to produce polyester attempts to improve the mechanical performance offibers as a synthetic replacement of silk. In general aliphatic polyesters have been reported. Most often,though, his products contained a considerable portion these approaches involve the addition of aromaticof dimers and oligomers next to linear polyesters, moieties to the polymer structure, in the pendantand the molecular weight of the latter would not groups or in the main chain. Besides structural


Fig. 4. Some of the most common diacid monomers used for polyester preparation.

rigidity, aromaticity brings about hydrophobicity and TPA units in the polymer backbone [56]. Anotherhence a marked decrease in the biodegradability [53] approach to the addition of aromaticity in polyesterswhich must be considered a serious flaw if non- involves the copolymerization of aliphatic diacidssustainability is desirable for environmental or medi- and diols with styrene glycol, resulting in aliphaticcal reasons. A simple way of introducing aromatic backbones such as PBS and poly(ethylene adipate),moieties is the copolymerization of aliphatic and PEA, with a small fraction of randomly distributedaromatic diacids with diols. For instance, random pendant aromatic groups [57]. The introduction ofand block copolymers of terephtalic acid (TPA), styrene glycol units into the polyester backbone didsebacic acid (SA), AAc, and 1,3-propanediol by not bring any improvement of mechanical propertiespolycondensation [54]. The rate of in vitro degra- but decreased the tensile properties and the degree ofdation decreased with increasing molar fraction of crystallinity. The biodegradability of PBS and PEATPA in the copolymers [54,55]. However, by op- was, however, not impaired. Similar results weretimizing the ratio of aromatic to aliphatic units in the obtained when introducing aromatic side groups bycopolymers, it was shown that good biodegradability copolycondensation of mandelic acid with BDO–could be maintained even at fairly high contents of succinic acid and ethylene glycol–AAc respectively


[58]. The degree of crystallinity, tensile strength, and beverages and is also widely used as a fiber aselongation decreased with increasing content of discussed in the next section. In the biomedical field,mandelic acid in PEA whereas tensile strength and PET is often the material of choice for permanentelongation actually improved for PBS. In both cases, vascular, abdominal, and ligament prosthesis. PBTthe biodegradability was rather enhanced than re- (Fig. 5b), prepared from TPA or its ester derivativetarded. The introduction ofn-paraffinic side groups and BDO, is similarly used a fiber but more exten-was another ineffective route to improve the me- sively used as an engineering thermoplastic. PBT ischanical performance of PEA. In this case, ethylene highly crystalline with good mechanical strength,glycol and AAc was polymerized in the presence of temperature stability, and dimensional stability. It is1,2-butanediol or 1,2-decanediol to introducen-ethyl also used for electrical applications thanks to itsor n-octyl branches, respectively. This modification good insulating properties. A common drawback ofof PEA caused a decrease in the degree of crys- PET and PBT is their limited heat resistance.tallinity, tensile strength, elongation and modulus It has been suggested that the use ofp,p9-biben-[59]. In contrast, the addition ofn-octyl branches to zoic acid, being a more rigid diacid than TPA, mayPBS was beneficial in the sense that elongation and bring about interesting properties of the resultingtear strength was improved. polyester, such as increased thermostability and/or

The most straightforward route to improve me- liquid crystallinity. A series of polyesters was pre-chanical properties, and to minimize the hydrolytic pared fromp,p9-bibenzoic acid and glycols having 4,instability when degradation is uncalled for, is the 6, 8 or 10 methylene groups, respectively. The firstintroduction of aromatic units into the polyester main two were found to exhibit thermotropic Smectic Achain. This is why TPA is such a tremendously phases [60]. When the study was extended to includeimportant building block in commercial thermoplas- also analogous polyesters derived from glycols withtic polyesters. TPA is a key building block in and odd number of methylene units, it was foundpolyethylene terephtalate (PET) and polybutylene that all products, where glycols of 4–9 methyleneterephtalate (PBT), the most important of the ther- units were used, were in fact able to form Smecticmoplastic polyesters on the market today. Thermo- mesophases [61]. A distinct odd–even behavior ofplastic polyesters typically find use as fibers, films, the izotropization temperature and layer thicknessand molding compounds. PET (Fig. 5a) is prepared with respect to the number of intervening methylenefrom TPA, or is ester derivative, and ethylene glycol groups in the glycol unit was observed. Succeedingin a two-step bulk polycondensation process. PET studies showed that the odd–even behavior could becrystallizes upon heating and/or orientation and explained by the fact that poly(p,p9-bibenzoate)saffords high-strength films that find use in photo- based on even-numbered glycols formed Smectic Agraphic films, insulation, and magnetic tape. PET has phases while their odd-numbered analogues formedfound widespread use as bottles for carbonated Smectic C2 phases [62,63]. Related polyesters were

synthesized from dimethylp,p9-bibenzoate, AAc andaliphatic glycols with 3, 4, 5 or 6 methylene groups[64]. A monotropic smectic mesophase was detectedfor the polyesters that were derived from 1,6-hex-anediol and had an AAc:glycol ratio ofx:1.4 wherexdid not exceed 0.4.

The polycondensation of TPA and IPA, or theirester derivatives, with bisphenol A affords amor-phous aromatic polyesters, generally referred to aspolyarylates [65,66], see Fig. 6. The polyarylates areexcellent engineering polymers, displaying thermalstability, strength, toughness, and creep resistance.Fig. 5. Thermoplastic polyesters of major commercial importance:Being heat resistant, the polyarylates typically find(a) Polyethylene terephtalate, PET, and (b) Polybutylene terephta-

late, PBT. use in electrical and mechanical components in


afforded network polyesters when polymerized withpolyols such as 1,1,1-trimethylolethane, 1,1,1-tri-methylolpropane, 1,2,3,4-butanetetrol [72].

Industrially, crosslinked polyester materials aremade from IPA or fumaric acid (FA) and unsaturated

Fig. 6. General structure of polyarylates. dianhydrides such as maleic anhydride or phtalicanhydride. In a first step, oligomeric resins areprepared by bulk condensation of a diacid, unsatu-rated anhydride and diol mixture. The resin is

consumer goods, such as hair dryers. However, subsequently glass fiber reinforced and crosslinkedprocessing of polyarylates presents a problem due to with styrene in a free radical initiated vinyl poly-their poor solubility and high softening temperatures. merization. Reinforced polyester networks of thisThe introduction of halogen substituents on the kind are popular construction materials in marine andphtalic acid moiety may have a favorable effect on automotive applications.the polyarylate solubility, as they do in the case ofaromatic polyamides. 2,5-Difluoroterephtalic acidhas been shown to be a particularly interesting 2 .1. Polyester fibersmonomer for this purpose [67]. 2,5-Difl-uoroterephthalic acid has been synthesized and poly- Polyester fibers constitute the lion’s share of themerized with either bisphenol A, any of several noncellulosic synthetic fibers consumed nowadays,derivatives of bisphenol A, or aliphatic diols, to finding major use in clothing, home furnishings andafford a series of fluoro containing aromatic polyes- tire cord. Thermoplastic, aromatic polyesters are wellters [68]. The introduction of fluoro groups did not suited for fiber purposes as they can be made linear,impair the thermal stability of the polyarylates, while symmetric, orientable by drawing, with molecularanalogues prepared from aliphatic diols showed weights over 10 000, and dyed, properties all neces-much less stability. 2,5-difluoroterephthalic acid has sary to make a good fiber. The commercial successalso been used for the preparation of related ther- of polyester fibers is easily explained by their wash-mally stable thermoplastics such as poly(arylene and-wear properties, heat stability, and resistance toether)s [69]. wrinkling, making them superior to cotton and wool.

Unsaturated and polyfunctional diacids are used The polyesters initially prepared by Carothersfor the preparation of network polyesters. For in- were aliphatic and obviously not suitable for fiberstance, malic acid (MA) is a diacid bearing a production because of their hydrolytic instability.hydroxy group that can participate in condensation Instead, it was the commercial availability of purereactions affording a polyester network. Both stereo- xylene isomers that made way for the thermoplastic,isomers,L- and D-malic acid, were investigated for aromatic polyesters.p-Xylene is readily oxidized bythe preparation of biodegradable optically active air to yield TPA, a monomer of great importance innetwork polyesters together with diols of different the industrial production of polyesters. Fibers fromnumber of methylene groups [70]. The polymers PET, prepared by melt spinning, were commercial-formed good films and were degradable in the ized by Du Pont in the early 1950s under the tradepresence ofRhizopus delemar lipase. In a similar names Dacron and Terylene. PBT was commercial-study, network copolyesters were prepared from ized in the 1970s. Kodel fibers, polydihydroxy-glycerol and SA with 10–90 mol.% of either suc- methylcyclohexyl terephthalate, are also made fromcinic acid, 1,12-dodecanedicarboxylic acid, 1,18-oc- TPA and used primarily for home furnishing fabrics,tadecanedicarboxylic acid, or TPA. These polyester just like PBT. PET fibers also find major use innetworks were also degradable mediated byRhizopus apparel. Lately, PET fibers have become used fordelemar lipase [71]. Other aliphatic diacids, con- biomedical purposes in the production of artificialtaining different numbers of methylene groups, also blood vessels.


2 .2. Enzymatically derived polyesters dicarboxylic acids or their derivatives as monomers[17,18]. A linear polyester product is however not

Enzymes such as lipases may cause hydrolytic guaranteed. On the contrary, cyclic esters, mainlydegradation of polyesters [34] but they may also be mono- and dilactones, may constitute the lion’s shareutilized for synthetic purposes. Recently, enzyme- of the yield during lipase-mediated polycondensationmediated synthesis of polyesters has gained increas- of diols and diacids [81]. When using lipases froming attention. Enzymatic polyesterification of diacid Candida cylindracea, Pseudomonas sp., or porcinemonomers in many cases offers superior control and pancreas as catalysts in the reaction between variousspecificity compared to conventional condensation aliphatic diacids and diols in organic media (Fig. 7),polymerization. Also, polymers can be afforded a mixture of linear and cyclic products was obtained,under milder conditions. Lipases (triacylglycerol the latter favored at higher reaction temperatureshydrolases), enzymes that catalyze the hydrolysis of (55–758C) [81].fatty acids, have been studied for this purpose[17,18]. Liposyme IM-20, a lipase fromMucormiehei has been used to polymerize a stoichiometric 3 . Poly(ester–amide)sAAc–BDO system [73] as well as a SA–BDOsystem [74]. Later, lipase B fromCandida antar- Polyamides are polymers with amide linkages inctica, immobilized as Novozym 435(R), was shown their main chain, resulting from the condensationto provide superior efficiency [75]. While the former reaction of diamines with dicarboxylic acids orprocesses were carried out in diisopropyl ether, diacid chlorides. If, instead of diacid monomers,results suggest thatCandida antarctica favors a carboxylic terminated polyester macromers preparedstep-growth mechanism under solvent-free condi- in the excess of diacid monomers are used, the resulttions. Solvent-free polyesterification of SA and BDO is a poly(ester–amide) composed of ester blockswas achieved usingCandida antarctica lipase [76]. linked through amide bonds, as schematically illus-Furthermore, Novozym 435 was shown to be effi- trated in Fig. 8. Property-wise, there are clearlycient for aromatic polyester synthesis from diacid synergistic effects involved with the preparation ofand diol monomers such as isophthalic acid (IPA) poly(ester–amide)s, that is the combination of esterand 1,6-hexanediol [77] and for a regioselective and amide moieties in a polymer backbone. Poly-polyesterification of glycerol and AAc [78]. Another amides generally display better mechanical andenzymatic route to aromatic polyesters involved IPA, thermal endurance than corresponding polyesters,TPA, and p-phenylene diacetic acid monomers, thanks to the formation of strong hydrogen bondingwhich was turned into divinyl esters and polymerized between the amide linkages of individual chains.with diols in the presence ofCandida antarctica Polyesters, on the other hand, are generally superiorlipase [79]. Likewise, the polyesterification of the in flexibility, solubility, and hydrolytic susceptibility,dicarboxylic acid–divinyl esters divinyl sebacate and and can thus be designed to degrade within adivinyl adipate with BDO was shown to be effective- reasonable time-scale making them useful for variously catalyzed by lipases from eitherCandida antar- biomedical and environmental applications. Obvious-ctica, Mucor miehei, Pseudomonas fluorescens, or ly, the combination of polyester and polyamidePseudomonas cepacia in organic media [19]. moieties leaves us with tremendous opportunities of

Other lipases useful for polyesterification include tuning the resulting polymer properties to fit aPseudomonas aeruginosa lipase, Candida cylin- desired profile, being strong, yet degradable enoughdracea lipase, andKlebsiella oxytota lipase. All of to be interesting in a biomedical context. Degra-these, as well asPseudomonas cepacia lipase, were dation of poly(ester–amide)s has been shown to takeeffective in catalyzing the polyesterification of SA place essentially by cleavage of the ester linkages,and 1,8-octanediol in aqueous medium [80]. leaving the amide segments more or less intact.

All in all, lipase-mediated polymerization has been Many synthetic routes to poly(ester–amide)s haveproven an efficient route to polyesters using various been proposed. An early approach involves the


Fig. 7. Lipase catalyzed condensation of aliphatic diacids and diols.

Fig. 8. General synthesis path for the preparation of poly(ester–amide)s.

amide-ester interchange reaction between a poly- medium and the biodegradation rate was found toamide and a polyester at high temperatures [82]. decrease with increasing nylon content. Early reportsSuch poly(ester–amide)s were prepared from PCL of poly(ester–amide)s also include products derivedand nylons of various lengths at 2708C in the from dicarboxylic acids, diols and diamines [83], orpresence of zinc acetate. Their biodegradability was diacids and bis-oxamidodiols [84]. A more general-evaluated in aRhizopus delemar lipase-containing ized procedure was later patented, involving the


copolymerization of diacids with diols and diamines with their parent constituents [89]: The poly(ester–to produce slowly degrading materials, having ab- amide)s were intermediate to the correspondingsorbable surgical devices as a particular application polyesters and nylons in terms of solubility, strength,in mind [85]. The bulk reaction of cyclic dicarboxy- and modulus, and could be oriented to fibers. Thelic acid anhydrides, bis(oxazoline)s, and diols prepoly(ester–amide)s show faster hydrolysis rate insents a neat synthetic pathway to poly(ester–amide)s. vitro that the parent polyesters, a somewhat surpris-a,v-Dicarboxylic acid monomers are hereby gener- ing result that was attributed to the lower degree ofated in situ as the cyclic anhydrides react with the crystallinity of the former. However, no enzymaticdiols, and afford poly(ester–amide)s via electrophilic degradation was observed, either in the presence ofattack at the nitrogen atom of the bis(oxazoline)s lipases or by papain, whereas the parent polyestersfollowed by ring-opening [86]. The same route was were markedly degraded in the same environmentused to prepare poly(ether–ester–amide)s by em- [89]. These findings are in fact representative forploying poly(ethylene glycol) as a comonomer. The many degradation studies of poly(ester–amide)s. Thedegree of polymerization is however impaired by hydrolysis rate of aliphatic poly(ester–amide)s mayeven the slightest deviation from accurate stoichiom- be ever so facile in vitro, they are still only little oretry. To overcome this, a modified synthesis route not at all biodegradable by enzymatic promotion.based on 1,3-oxazolies and cyclic dicarboxylic an- To circumvent the problem of limited biodeg-hydrides was proposed [87]. Both approaches de- radability, amino acid units have successfully beenscribed above offer versatility, in that the properties incorporated into the backbone of poly(ester–amide)sof the resulting polymer, e.g. theT , can be varied to enhance the bioanalogy of the chain structure, thusg

over a broad range by varying the structure of the making it more attractive for enzymatic attack. Fordicarboxylic monomers. However, the molecular instance, the amino acids glycine, lysine and phenyl-weights obtained are limited, due to formation of alanine were separately copolymerized with AAc andimide byproducts. 1,2-ethanediol to form poly(ester–amide)s of which

The beneficial combination of properties in poly- the two latter were degradable by proteolitic en-(ester–amide)s was taken advantage of in the de- zymes [90]. Similarly, poly(ester–amide)s were de-velopment of new thermoplastic materials with good rived from 1,6-hexanediol, SA, and any of the aminomechanical performance, processability and yet full acids alanine, phenylalanine, and glycine [91].biodegradability [88]. Such a family of poly(ester– Glycine was also used for the copolymerization withamide)s was commercialized under the trade name of 1,6-hexanediol and diacids with methylene groupsBAK in the mid 1990s. There are a number of BAK ranging from 2 to 8 to prepare a series of aliphaticpolymers on the market today, e.g BAK1095 derived poly(ester–amide)s [92] with low molecular weightsfrom caprolactam, AAc, and BDO, or BAK2195 that were readily biodegraded by papain enzymes.combining blocks of polyamides from hexa- Since the beginning of the 1990s, the synthesis ofmethylenediamine and AAc with block of polyesters stereoregular polyamides has gained interest becausefrom AAc and BDO. BAK poly(ester–amide)s can of their potential as materials for biomedical applica-and have been used for a number of applications tions. (2R,3R)-L-tartaric acid (Fig. 9) is an attractivewhere disposable materials are preferred. The effects monomer in this respect, being a naturally occurringof combining polyester and polyamide moieties has substance with two chiral carbon atoms [93]. Twofurther been demonstrated for poly(ester–amide)sprepared by polycondensation of polyester macrom-ers derived from SA and 1,6-hexanediol or 1,12-dodecanediol (polyester 6,10 and polyester 12,10,respectively), and polyamide macromers derivedfrom sebacoyl chloride and 1,6-hexanediol or 1,12-dodecanediol (nylon 6,10 and nylon 12,10, respec-tively) according to the synthesis scheme in Fig. 8. Fig. 9. Structure ofL-tartaric acid; (2R,3R)-(1)-2,3-dihydroxy-These two poly(ester–amide)s were then compared butanedioic acid.


families of poly(ester–amide)s were accordingly linkages, so that the bioactive substance is releasedprepared from di-O-methyl-L-tartaric acid and suc- in time [99]. Polyesters of malic acid have also beencinic acid. The first one was synthesized by poly- recognized as promising prodrug backbones. Thecondensation in chloroform of ester trimers of 1,6- pendant carboxylic groups of the poly(malic acid)hexanediol and succinic anhydride withL-tartaric main chain was covalently coupled to the anti-canceracid and trimethylsilyl-activated 1,6-hexanediamine, drug adriamycin via amide or ester bonds. Theresulting in random copolymers with varying con- cytotoxic activity of these prodrugs was evaluated intents of ester groups [94]. Hydrophilic and degrad- vitro [100].able poly(ester–amide)s were obtained. As could beexpected, the modulus, strength,T , and T de-m g

creases as the content of ester groups increased while4 . Poly(ester–imide)sthe rate of hydrolytic degradation increased. Thesecond family was prepared from succinic acid,L- Polyimides have been widely studied for manytartaric acid, andn-amino-1-alcohols with varying years thanks to their thermal stability, mechanicallength of methylene segments, resulting in alternat- strength and good electrical properties. A drawbacking isotactic copolymers with equal amounts of is however their poor solubility in most organicamide and ester groups [95]. Hydrophilic but non- solvents which, in combination with high tempera-water soluble poly(ester–amide)s were obtained ture resistance, impair the processability of manywhere T , and T decreased as the number of polyimides. To circumvent this problem copolymersm g

methylene groups in the amino alcohol units in- of polyesters and polyimides have been studied.creased. Another approach to obtain stereoregular Imide segments have also been incorporated intopoly(ester–amide)s involved the polycondensation of crosslinkable polyesters for the purpose of increasingdiacids and optically active amino alcohols, such as the heat stability of resins and varnishes. Several2-amino ethanol and leucinol. Polymers derived from strategies in synthesizing poly(ester–imide)s havethe former were hydrolytically degradable [96]. been presented [101]: (a) polycondensation ofHydrolytic degradability was also demonstrated for bisimide dicarboxylic acids, derived from trimelliticpoly(ester–amide)s prepared from optically active acid and a diamine, with diols, (b) polycondensationa,v-amino acids with intervening ester groups de- of diacids containing an imide group with diols, (c)rived from carbohydrates such as arabinitol and reaction between diamines with an ester containing axylitol [97]. Optically active poly(ester–amide)s dianhydride group, (d) polycondensation of diols andhave also been prepared from diols derived from diacids with 4-carboxy-N-(hydroxy-chiral amino alcohols [98]. Four diol monomers were phenyl)phthalimide, and (e) imide-forming condensa-synthesized by condensation reactions of dicarboxy- tion reactions between a polyamine and an anhydridelic acids (SA or AAc) with amino alcohols (L- ‘connector’ [102].phenylalaninol orL-leucinol). The diol monomers An extensive series of poly(ester–imide)s havewere later polycondensed with any of the mentioned been prepared by Kricheldorf et al., their commondiacids in the presence of a catalyst. The number of feature being that they exhibit liquid crystalline (LC)methylene groups in the diacid moiety was proved to mesophases. Firstly, poly(ester–imide)s were pre-have a significant effect on the thermal properties of pared by direct polycondensation ofN-(49-acetox-the resulting poly(ester–amide)s. yphenyl)-4-acetoxyphtalimide witha,v-diacids hav-

The combination of ester and amide linkages in a ing different number of intervening methylenepolymer has been used for the preparation of poly- groups, yielding semi-rigid products (Fig. 10). Thesemeric prodrugs, starting from tyrosine end-function- poly(ester–imide)s exhibit nematic liquid crystallinealized oligomers of poly(ethylene glycol). The hy- mesophases above the melting point, a layereddroxy groups of the tyrosine units were polycon- crystalline phase in the solid state and an odd–evendensed with SA and the terminal NH groups were behavior with respect to isotropization and glass2

linked to a model drug (benzoyl chloride). Degra- transition temperatures [103,104]. The longer thedation was shown to proceed by cleavage of the ester methylene spacer in the diacid units, the higher the


sequently was polycondensed with bisphenol A.Poly(ester–imide)s with fairly high thermal stabilityand good solubility were obtained [109]. In thepreparation of a series of thermoplastic elastomers,trimellitic anhydride was reacted with 1,4-butanediamine to form a bisimide dicarboxylic acid

Fig. 10. Typical structure of poly(ester–imide)s derived from monomer, which in turn was polycondensed withvarious aliphatic dicarboxylic acid monomers (n53–12,14 or 20) BDO and hydroxy terminated poly(tetramethylene[103,104].

oxide)s of various molecular weights [110]. The aimwas to obtain poly(ether–ester–imide)s that would

segmental flexibility and the more is the formation of microphase separate into hard imide-containing do-a crystalline state favored at the expense of the mains and soft ether domains. However, only whennematic phase [104]. An isomeric series of poly(es- using poly(tetramethylene oxide) with a molecularter–imide)s derived fromN-(4-carboxyphenyl) tri- weight of 650 Da was a satisfactory result obtained,mellitimide anda,v-diols on the other hand, never while poly(tetramethylene oxide)s of 1000 Da orshow nematic behavior but can adopt smectoid more showed macrophase separation during thephases in the solid state [105]. Similar smectic layer polycondensation process, resulting in matrices withstructures in the solid state have been observed in a incomplete interaction between hard and soft seg-range of related poly(ester–imide)s. For instance, ments and thus poor mechanical properties. To avoidbisimide dicarboxylic acid monomers were prepared macrophase separation, an analogous series of poly-from trimellitic anhydride and a diamine such as (ether–ester–imide)s were prepared using poly-3-methyl-1,5-diaminopentane and polycondensed (ethylene oxide) instead of, or in combination with,with an acetylated diphenol (e.g. acetylated 2,6- poly(tetramethylene oxide) [111]. Poly(ethylenedihydroxynaphtalene) [106]. Polycondensation of oxide) based poly(ether–ester–imide)s of this kindanother mesogenic unit,N,N9-bis(4-propionyl-oxy- did not show macrophase separation and displayedphenyl)biphenyl-3,39,4,49-tetracarboxylic diimide, good mechanical behavior.with aliphatic diacids also led to the formation of While the literature of poly(ester–imide)s withpoly(ester–imide)s capable of forming smectoid liquid crystalline behavior is extensive, studies onphases, both in the molten and in the crystalline state poly(ester–imide)s for biomedical applications are[107]. Trimellitic anhydride has also been used by scarce. This can be explained by the semi-rigidother authors for the preparation of liquid crystalline nature and resistance toward biodegradation of poly-poly(ester–imide)s [108]. A diacid monomer was (ester–imide) chains.prepared from trimellitic anhydride and 1,6-hex-anediamine and polycondensed withp-hydroxy-benzoic acid and various aromatic diols to form a 5 . Poly(ester–urethane)sseries of poly(ester–imide)s. However, only thoseprepared from linear diphenols or diphenols with Poly- or oligoesters can be synthetically designedsmall substituent groups exhibited thermotropic li- to bear hydroxy groups at their chain ends and arequid crystalline behavior, as in the case of bis-(4- then, in effect, macrodiols. Such polyester diols arehydroxylphenyl)ketone giving rise to poly(ester–im- useful macromers in the preparation of poly-ide)s with nematic mesophases. urethanes, a preparation path of which is schemati-

Trimellitic anhydride is a popular starting material cally illustrated in Fig. 11. The use aliphatic polyes-for poly(ester–imide)s, not only for the preparation ter macrodiols, as well as polyether diols, has beenof liquid crystalline polymers. For instance, trimel- of tremendous importance in the commercial de-litic anhydride was reacted with 4,49- velopment of new polyurethane materials as theydiaminodiphenyl ether, 6-aminocaproic acid,p- allow for the incorporation of flexible segmentsaminobenzoic acid, orm-aminobenzoic acid to form between rigid aromatic diisocyanates. The initialbisimide dicarboxylic acid monomers which sub- poly(ester–urethane) polymer formed by polycon-


Fig. 11. Schematic illustration of a preparation route to poly(ester–urethane)s.

densation may in a second step be chain extended Estane polymers may be turned in to an advantage,with additional diisocyanate monomers and as in the case of the preparation of porous implantsdiamines. The result is a block copolymer consisting as temporary scaffolds for the reconstruction ofof soft (polyester–urethane) and hard (polyurethane- meniscus lesions [118].amide) segments. Such poly(ester–urethane)s exhibit The use of polyester macrodiols in polyurethanea typical two-phase morphology, characterized by a production however offers even greater versatility. Insemicrystalline rigid phase dispersed in a soft, trans- addition to thermoplastic elastomers, covalentlyparent phase, and behave in effect like a physically crosslinked networks may be prepared by reactionscrosslinked thermoplastic elastomer. This very route with urethane linkages by any of three methods.is employed for several commercially available Firstly, the poly(ester–urethane) may be prepared inelastomeric polyurethanes, typically those that con- an excess of diisocyanate, leading to an addition ofstitute flexible fibers such as Du Pont’s Spandex. isocyanate groups to the nitrogen of urethane link-PEA is a common polyester macrodiol used for this ages in the polymer backbone and the formation ofpurpose, while toluenediisocyanate (TDI) and allophonate crosslinks (Fig. 12a). Secondly, if poly-methylene-4,49-diphenyldiisocyanate (MDI) repre- ester marcodiols prepared by copolycondensationsent typical diisocyatate monomers. The exact prop- with some polyfunctional alcohols are used, theerties of the poly(ester–urethane)s can in a facile pendant hydroxyl groups provide sites for additionalway be tuned by means of segment length and reactions with diisocyanate monomers affording astructure. Thus, poly(ester–urethane)s may come as network with urethane crosslinks (Fig. 12b). A thirdanything from soft and hard foams to elastomers, method involves the preparation of poly(ester–adhesives, coatings, thermoplastics, and molding urethane) in an excess of diisocyanate to give ancompounds. Estane polymers are typical examples of isocyanate end-functionalized product. As the enda commercially available poly(ester–urethane)s com- groups react with atmospheric water, chain extendedposed of hard and soft segments [112]. Estane 5703 polymers with urea linkages are formed. Furthercontains aliphatic ester blocks of poly(butylene reactions with free isocyanate groups lead to headipate), derived from AAc and BDO, which is chain formation of biuret crosslinks (Fig. 12c). This tech-extended with BDO and copolymerized with MDI nique is often employed in ‘one-pot’ poly(ester–[113]. Estane 5703 is known to degrade over time, urethane) coating formulations. An alternative pathaffecting its long-term mechanical properties. The to the ones just described is the incorporation ofprocess of hydrolysis has been closely studied by unsaturated carbon–carbon bonds in the structure,means of infrared linear dichroism [114] and through and the subsequent curing to form a covalentlywater absorption and diffusion measurements [115]. crosslinked network. Apart from the wide range ofEstane has found commercial use as binder matrices commercial poly(ester–urethane)s available, there isin plastic-bonded explosives (PBXs) and in pro- an array of poly(ester–urethane)s described in litera-pellants [116,117], where the degradability is consid- ture, those of which are derived from dicarboxylicered a short-coming. The lack of biostability of acid monomers will be of concern in this review.


Fig. 12. Crosslinking reactions of poly(ester–urethane)s: (a) the formation of allophonate linkages, (b) the formation of urethane linkages,and (c) the formation of biuret linkages.

One way to incorporate unsaturations into the zation of various poly(ester–urethane)s has beenpoly(ester–urethane) backbone is the use of an frequently studied. Incorporation of alkyl side chainsunsaturated diol or an unsaturated diacid in the into the poly(ester–urethane) structure was proven apreparation of the polyester macrodiol.cis-2-Butene- viable route to increasing the hydrolytic and thermal1,4-diol has been utilized for this purpose [119,120]. stability of poly(ester–urethane)s. The side chainsFor instance, a polyester macrodiol was prepared were in this case incorporated by using branchedfrom a series of short aliphatic diacids, e.g. AAc, oligoesters, e.g. poly(2,4-diethyl pentamethyleneSA, and pimelic acid, andcis-2-butene-1,4-diol. The adipate)glycol, as the hydroxy terminated macromersAAc based polyester macromer and MDI was then in a polycondensation reaction with MDI [123].polycondensed to form a graftable or crosslinkable Although less sensitive toward weathering thanpoly(ester–urethane). The incorporation of azo chro- poly(ether–urethane)s, poly(ester–urethane)s aremophores into poly(ester–urethane) backbones has known to undergo UV-induced oxidation that maybeen reported. Poly(tetramethylene adipate), derived cause miscoloring and ultimate failure. It is hypothe-from AAc and BDO, was used as the polyester sized that the ester groups play a negligible role inmacrodiol and reacted with either TDI or MDI to that respect. Instead, methylene groups in thea

form prepoly(ester–urethane)s that, in a subsequent position to the N–H in the urethane functionality arestep, were chain extended with 1,2-ethanediamine oxidized starting a chain reaction the leads toand 4,49-diaminoazobenzene. The resulting products backbone chain scission and thus polymer degra-were poly(ester–urethane)s with azo chromophores dation [124].in the randomly distributed hard segments [121]. In More recently, the degradability of poly(ester–this case, no photoisomerization was detected, while urethane)s has been reassessed and considered anlight-induced photoisomerization readily took place advantageous property, especially for biomedicalwhen the azo chromophore was incorporated in the applications. Polymers derived from renewable re-soft polyester segment [122]. sources, also known as ‘green’ polymers, are gaining

The long-term stability of poly(ester–urethane)s increasing attention due to the escalating environ-has for a long time been a concern since they are mental problems with polymer waste management. Asusceptible to hydrolytic and enzymatic degradation ‘green’ poly(ester–urethane) has been prepared fromas well as oxy-, thermo- and mechanical degradation 1,3-propanediol and SA [125]. The monomers werewhich eventually may cause material failure in a polycondensed to form a hydroxy terminated estergiven application. Thus, the degradation and stabili- macromers of various lengths and later the chain


extended in the presence of MDI and additional hydrogenated derivative [130]. Also recently, seg-1,3-propanediol in accordance with the general syn- mented poly(ester–urethane)s based on poly(´-cap-thetic pathway described in Fig. 11. The resulting rolactone) as the ester moieties have gained attentionpoly(ester–urethane)s consist of hard and soft seg- as environmentally friendly polymers [131].ments and display mechanical properties that match The biodegradability of poly(ester–urethane)s isthose of other common thermoplastics used in com- interesting from an environmental point of view butmodity production. is of equal interest for biomedical applications. In

Poly(ester–urethane)s are degradable by several fact, a number of polyurethane based materials aremechanisms of which hydrolytic chain scission is the used in a biomedical related context, e.g. poly(ester–single most important one. Ester groups are more urethane)s, poly(ether-urethane)s, and poly(car-hydrolytically susceptible than the urethane linkage bonate-urethane)s. The latter is more frequently[126], suggesting that biodegradation of poly(ester– becoming the polyurethane of choice when perma-urethane)s proceeds via firstly the hydrolysis of ester nent aids are needed as their biodegradation rate islinkages and secondly the assimilation of polyester markedly retarded as compared with their ester andfragments by microorganisms. The urethane seg- ether based analogues. The only viable mechanismsments are believed not to be bioassimilated at all. of degradation in vivo are oxidation and hydrolysis,Hence, the rate of biodegradation can be tuned by and a combination of these two will mediate themodifying the length and structure of the ester material deterioration of poly(ester–urethane) im-segments. The rate of hydrolysis is dependent on the plants. In vivo oxidation is typically mediated by thematrix permeability to water, the flexibility of the action of macrophages. Oxidation in combinationester segments and the chain distance between ester with mechanical stress and hydrolysis may causegroups, that is the water absorption varies from one material deterioration by environmental stress crack-poly(ester–urethane) to another depending on the ing of implants. Polycarbonate based polyurethaneschemical structure, but the rate of diffusion of water have shown superior resistance toward oxidationin the matrix seems not to be a rate-limiting step in [132], as illustrated by a comparative study ofthe hydrolysis process unless the matrix is cross- different polyurethane based vascular grafts [133].linked [127]. The microbial action is closely con- As far as in vivo hydrolytic degradation isnected to the nature of the species present. Bacterial concerned, the structure of both the ester and thedegradation is mediated through the activity of urethane segments will influence the rate of such inexcreted enzymes. A pure strain of gram-positive vivo hydrolytic degradation [126]. This was illus-nonsporulating bacteria was shown to degrade the trated for a series of poly(ester–urethane)s based onester segments of poly(ester–urethane)s in which the MDI and esters derived from AAc and aliphaticester block was composed of polyethylene succinate glycols of various length; The higher the content ofor polybutylene adipate and trimethylhexamethylene methylene groups in a repeating ester unit, thediisocyanate, MDI, or a combination of tri- slower the rate of hydrolysis [134]. These adipatemethylhexamethylene diisocyanate and 2-methyl-1,5 based poly(ester–urethane)s were intended for tem-pentanediamine were used as the urethane block porary biomedical use as nonadhesive films for themonomers [128]. The rate of degradation was closely prevention of postsurgical adhesions [134]. In agree-connected to the rigidity of the urethane blocks, as ment, the higher the ester portion of a poly(ester–well as the polyester segment mobility. Bacteria urethane) derived from PEA, MDI and BDO, thebelieved to be a species ofCorynebacterium were higher their water absorption [135].not prone to degrade a tested poly(ester–urethane)but used an added yeast extract as the primary sourceof nutrition, leaving the polymer somewhat degraded 6 . Poly(ester–anhydride)sas a result of co-metabolism [129]. To facilitate thebiodegradation rate, up to 70% of starch was intro- Poly(ester–anhydride)s are polymers composed ofduced into the matrices of poly(ester–urethane)s alternating segments of ester and anhydride moietiesderived from AAc, ethylene glycols and MDI or is in the polymer backbone. A general synthetic path to


Fig. 13. General synthetic pathways to poly(ester–anhydride)s.

poly(ester–anhydride)s involves polycondensation in bis(4-carboxyphenyl urethane)s with alkane or oxy-three steps, as schematically illustrated in Fig. 13. alkane moieties were used as the diacid monomers.Firstly, diacid and diol monomers of choice are These were converted to anhydride end-function-reacted to form an oligo- or polyester macromer alized monomers via the reflux condensation withbearing carboxylic acid end-groups. Secondly, the acetic anhydride and then melt condensed to formester macromer end-groups are converted to an- poly(anhydride–urethane)s [137]. A comparativehydride groups by briefly refluxing the macromer in degradation study showed no significant difference inacetic anhydride. In the last step, melt polycondensa- the mass loss rate between corresponding poly-tion of the ester–anhydride prepolymers affords a (anhydride)s containing urethane or ester segments,poly(ester–anhydride) product. Alternatively, the respectively. Another series of degradable poly(es-ester–anhydride prepolymers may be melt condensed ter–anhydride)s intended for drug carriers and pro-with other anhydride prepolymers forming a seg- drugs has been prepared fromp-hydroxybenzoic acidmented poly(ester–anhydride). and AAc [138]. AAc was converted into adipic

The ester and the anhydride backbone function- anhydride [139] and reacted withp-hydroxybenzoicalities both are susceptible to hydrolytic cleavage and acid to form a diacid end-functionalized monoester.have individually been widely utilized in the prepara- This monoester was used as a monomer in thetion of degradable biomedical materials. When com- preparation of a high poly(ester–anhydride), usingbined, the poly(ester–anhydride)s offer tremendous the conventional two-step polycondensation routeversatility as the structure and degradation time can with acetic anhydride described earlier. A corre-be varied over a broad range. Hence, a variety of sponding copoly(ester–anhydride) was likewise pre-poly(ester–anhydride)s have been prepared as po- pared by copolymerization with a diacid end-func-tential candidates for drug delivery and other bio- tionalized monoester fromp-hydroxybenzoic acidmedical purposes. Following the general scheme for and sebacic anhydride. The same authors have alsothe preparation of poly(ester–anhydride)s, a series of reported on the use of a fluorophoric diacid,p-such polymers have been prepared from various (carboxyehtylformamido)benzoic acid, and SA in the4,49-alkane- and oxyalkanedioyldioxydibenzoic acids preparation of fluorescent poly(coanhydride)s. Such[136]. Later, a similar path was employed, in which materials may be used as fluorescent microspheres


for drug delivery applications [140]. Being natural 7 . Poly(ether–ester)sbody components, fatty acids may be advantageousbuilding blocks for degradable biomedical polymers. Poly(ether–ester)s are simply block copolymers ofA fatty acid, ricinoleic acid, was thus used for the ester and ether segments. The introduction of etherpreparation of degradable poly(ester–anhydride)s segments may be helpful in modifying the mechani-[141]. As ricinoleic acid is monofunctional, it was cal properties or tuning the degradation rate offirst esterified with maleic anhydride or succinic polyesters. Poly(ether–ester)s make good thermo-anhydride to produce nonlinear diacid monomers. plastic elastomers. It was early observed that co-These were converted to dianhydrides in the pre- polymerization of poly(ethylene glycol) and PETsence of acetic anhydride and subsequently polymer- could help reducing the crystallinity and increase theized with sebacic anhydride prepolymers. These hydrophilicity of the aromatic polyester, whichricinoleic-based poly(ester anhydride)s are fast de- would improve the dyability of PET fibers [147]. Agrading and release incorporated drugs within 1 consequence of the introduction of polyethyleneweek. Drug delivery matrices of poly(ester–anhy- glycol blocks into the backbone of PET, was how-dride)s containing cycloalkane moieties in the poly- ever an increase in the hydrolytic susceptibilitymer backbone have also been proposed. 1,4-cyclo- causing the poly(ether–ester) to degrade within ahexanedicarboxylic acid was used as the diacid timescale of a few months. The biodegradability ofmonomer and converted to a dianhydride via the poly(ethylene glycol–co-ethylene terephthalate) ren-reflux condensation in acetic anhydride [142]. Sub- der it suitable for temporary biomedical applicationssequently, the prepolymers were melt-condensed [148,149]. The same goes for copolymers of PBTtogether with an aliphatic diol, either ethylene glycol, and poly(ethylene glycol), yielding poly(ether–es-1,3-propanediol, BDO, or 1,6-hexanediol to form ter)s with hard aromatic ester segments and soft etherhydrolytically degradable poly(ester–anhydride)s segments, behaving as thermoplastic elastomers[143]. These cycloalkane containing poly(ester–an- [150,151] with good biocompatibility in vivohydride)s displayed a surface eroding pattern and [152,153]. The PBT–poly(ethylene glycol) copoly-released an incorporated model drug within 5–15 mers have been investigated for several biomedicaldays depending on the lengths of the diol segments. applications including bone replacement [154], skinThe bioactive compound may alternatively be an substitution [153], and drug delivery [155]. Multi-integral part of the polymer backbone itself; A block copolymers of PBT and poly(ethylene glycol)poly(ester–anhydride) was recently prepared from were used for the preparation of microspheres andbenzyl salicylate and SA, the latter in a first step films intended for drug delivery applications. Afterconverted to sebacoyl chloride [144]. This polymer careful tuning of the microsphere preparation param-acts as a polymeric prodrug, releasing salicylic acid eters, matrices offering a controlled release of in-as a degradation product during hydrolysis in vitro. corporated bovine serum albumin was affordedThe prodrug was shown to degrade completely over [156]. The preparation of lyzozome-containing filmsa period of 3 months at neutral pH and hydrolyzed and microspheres of PBT–poly(ethylene glycol)considerably faster under basic conditions. The poly- multiblock copolymers was even more successful,(ester–anhydride) salicylic prodrug was next im- and a release pattern nearly following zero-orderplanted in the mouths of mice. A histopathological kinetics was obtained [157].study showed that the implants exhibited good Other poly(ether–ester)s have also been suggestedbiocompatibility and that they stimulated new bone as potential biomedical materials. For instance, sev-formation [145]. eral polymers were synthesized from 4-h2-[2-(2-hy-

Another series of poly(ester anhydride)s have been droxyethoxy)ethoxy]ethoxyjbenzoic acid, 4-h2-[2-(2-prepared from aromatic and aliphatic silylated diols hydroxyethoxy) ethoxy] - ethoxyj phenylaozobenzoic[146], although this polycondensation route involves acid and either 12-hydroxydodecanoic or 16-hy-diacid chloride monomers rather than dicarboxylic droxyhexadecanoic acid with the special applicationacids. of colon-specific drug release in mind [158]. The


copolymerization of poly(tetramethylene glycol) products being potentially biodegradable [164].ether blocks with poly(ethylene succinate) esters Similarly, ‘green’ poly(ester–carbonate)s were pre-resulted in poly(ether–ester)s [159] where the me- pared from 1,4:3,6-dianhydro-D-glycitol, 1,4:3,6-chanical properties and degradation rate could be dianhydro-D-mannitol, and 1,4:3,6-dianhydro-D-hex-varied by changing the content of ether blocks, the itol monomers which are readily available fromlatter increasing with higher mole fractions of poly- simple sugars in plant-based biomass [165–167].ether blocks [160]. These isomeric diols were polycondensed with ali-

A drawback of the popular biodegradable poly- phatic dicarboxylic acid units to form poly(ester–mers so frequently used throughout the biomedical carbonate)s that are potentially biodegradable byfield today, e.g. PLA and PLGA, is the lack of enzyme-mediated hydrolysis.pendant groups that allow for functionalization such Polybenzimidazoles are derived from dicarboxylicas the attachment of bioactive moieties. Recently, acid monomers and aromatic tetramines, that issome amino acids such as lysine and aspartic acid amine functionalized monomers where the amine-have been proposed as suitable building blocks that :acid ratio is 2:1 [168]. Polymerization typicallywould introduce functional side groups into bio- involves high reaction temperatures and proceeds indegradable polyesters. For instance, oligomers of two steps. Since diacids tend to decarboxylate at theaspartic acid (Fig. 4) was attached to PEG to form a higher temperatures required, diester derivates arepoly(ether–ester) block copolymer with multiple commonly used. The synthetic procedure typicallypendant carboxylic acid groups in the polypeptide involves a two-step melt polymerization where theblocks. Functionalization of the side groups with an monomers are first heated in an inert atmosphere toadriamycin-conjugate afforded a polymeric anti- form a solid prepolymer, which is finely groundedcancer prodrug [161]. Alternating copolymers ofL- and heated up to 4008C to produce high polymers.aspartic acid and PEG has also been prepared [162]. However, polymerization under milder conditionsThe N-protected aspartic acid was in this case first has been demonstrated where direct polycondensa-converted to an aspartic acid anhydride and then tion of diacids and 3,39-diaminobenzidine tetrahydro-polymerized with PEG. Subsequent deprotection of chloride is possible, provided that the reactions arethe amino group yielded poly(ether–ester)s with carried out in the presence of phosphorous pentoxidefunctional pendant groups that degrade by hydrolysis in methanesulfonic acid [169]. The reaction schemein vitro over a period of 1 month at neutral pH. is given in Fig. 14. Polybenzimidazoles are often

Numerous poly(ether–ester)s have been prepared colored and display good thermal and hydrolyticbearing mesogenic ester units in their main chain. stability.These polymers, which have been extensively re- Polybenzoxazoles and polybenzthiazoles are bothviewed elsewhere, display liquid crystalline behavior prepared in a manner similar to the polybenz-and have interesting mechanical and/or thermal imidazoles [170,171]. Polybenzoxazoles are derivedproperties, not in the least for thermoplastic en- from dicarboxylic acid monomers and bis(o-amino-gineering applications [163]. phenol)s or related compounds (Fig. 15a). Polyben-

zthiazoles are closely related to polybenzoxazolesand synthesized in a similar manner, using bis(o-

8 . Miscellaneous polymers derived from diacid aminothiol)s (Fig. 15b). Both families have highlymonomers aromatic, rigid backbones and represent materials of

excellent thermal stability that are used in fiber orIn the search for ‘green polymers’, a poly(ester– film applications. They are, however, not suitable nor

carbonate) has been prepared from succinic acid and investigated for in vivo biomedical applications such1,3-propanediol, which was polycondensed to form as drug delivery. Similar features apply to thehydroxy terminated ester macromers. The macromers poly(benzobisoxazole)s obtained from benzidineswere subsequently chain extended in the presence of and substituted diacid monomers, i.e. bisalkylthio-phosgene to produce high-molecular-weight flexible and bisalkoxy-terephtalic acid [172].


Fig. 14. Reaction scheme for the preparation of polybenzimidazoles from diacid monomers [169].

Fig. 15. Structure of (a) poly(p-phenylenebenzobisoxazole) and (b) poly(p-phenylenebenzobisthiazole).

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Polyesters based on diacid monomers