How the Aliphatic Glycol Chain Length Determines the Pseudoeutectic Composition in Biodegradable Isodimorphic poly(alkylene succinate-ran-caprolactone) Random Copolyesters.

We synthesize four series of novel biodegradable poly(alkylene succinate-ran-caprolactone) random copolyesters using a two-step ring-opening/transesterification and polycondensation process with ε-caprolactone (PCL) as a common comonomer. The second comonomers are succinic acid derivatives, with variations in the number of methylene groups (nCH2) in the glycol segment, nCH2 = 2, 4, 8, and 12. The obtained copolyesters were poly(ethylene succinate-ran-PCL) (ESxCLy), poly(butylene succinate-ran-PCL) (BSxCLy), poly(octamethylene succinate-ran-PCL) (OSxCLy), and poly(dodecylene succinate-ran-PCL) (DSxCLy). We discovered a new mixed isodimorphic/comonomer exclusion crystallization in ESxCLy copolymers. The BSxCLy, OSxCLy, and DSxCLy copolymers display isodimorphic behavior. Our findings revealed a significant variation in the pseudoeutectic point position, from mixed isodimorphism/comonomer exclusion crystallization to isodimorphism with pseudoeutectic point variation from 54% to up to 90%. Moreover, we established a link between the melting temperature depression slope variation and the comonomer inclusion/exclusion balance, providing valuable insights into the complex topic of isodimorphic random copolymers.

Enzymatic Degradation Behavior of Self-Degradable Lipase-Embedded Aliphatic and Aromatic Polyesters and Their Blends.

Over the past decade, the preparation of novel materials by enzyme-embedding into biopolyesters has been proposed as a straightforward method to produce self-degrading polymers. This paper reports the preparation and enzymatic degradation of extruded self-degradable films of three different biopolyesters: poly(lactic acid) (PLA), poly(butylene adipate-co-terephthalate) (PBAT), and poly(butylene succinate) (PBS), as well as three binary/ternary blends. Candida antarctica lipase B (CalB) has been employed for the enzyme-embedding procedure, and to the best of our knowledge, the use of this approach in biopolyester blends has not been reported before. The three homopolymers exhibited differentiated degradation and suggested a preferential attack of CalB on PBS films over PBAT and PLA. Moreover, the self-degradable films obtained from the blends showed slow degradation, probably due to the higher content in PLA and PBAT. These observations pave the way for exploring enzymes capable of degrading all blend components or an enzymatic mixture for blend degradation.

Disappearance of Melt Memory Effect with Comonomer Incorporation in Isodimorphic Random Copolyesters.

Melt memory effects in polymer crystallization have attracted much attention in the past few years. Although progress has been made in understanding how the chemical structure of polymers can affect melt memory, there are still some knowledge gaps. In this work, we study how incorporating a second comonomer unit that is partially included in the crystalline unit cell affects the melt memory effect of the major component in a random isodimorphic copolymer for the first time. This second comonomer unit depresses the melting temperature of the homopolymer, reduces the crystallinity, and distorts the crystalline unit cell. However, its effect on the stability of self-nuclei and the production of melt memory has not been studied so far. To this aim, we have selected poly[(butylene succinate)-ran-(ε-caprolactone)] random copolyesters PBS-ran-PCL that are isodimorphic, i.e., they exhibit a pseudoeutectic point. This point separates the formation of BS-rich crystals from CL-rich crystals as a function of composition. The results reveal that the melt memory effect of these isodimorphic copolymers is strongly reduced with the incorporation of even very small amounts of comonomer unit (i.e., 1 molar %). This indicates that the incorporation of a second comonomer unit in the polymer chain disrupts the intermolecular interactions present between the chain segments in the crystal lattice of the major component and reduces the capacity of the material to produce self-nuclei. This reduction is more drastic for copolymers in which the second comonomer unit is mostly rejected from the crystalline phase. Contrary to olefin-based copolymers, for copolyesters, the second comonomer unit eases the process to reach an isotropic melt state upon melting. This work reveals the impact of introducing comonomer units on the melt memory effect in isodimorphic random copolyesters.

Challenging Isodimorphism Concepts: Formation of Three Crystalline Phases in Poly(hexamethylene-ran-octamethylene carbonate) Copolymers.

In this work, poly(hexamethylene-ran-octamethylene carbonate) copolycarbonates were synthesized by melt polycondensation in a wide range of compositions. The copolymers displayed some of the characteristic isodimorphic thermal behavior, such as crystallization for all the compositions and a pseudoeutectic behavior of the melting temperature (Tm) versus composition. The pseudoeutectic point was located at 33 mol % poly(octamethylene carbonate) (POC) content (i.e., corresponding to the PH67O33C copolymer). Surprisingly, the crystallinities (Xc) for a wide range of copolymer compositions were higher than those of the parent components, a phenomenon that has not been observed before in isodimorphic random copolymers. The structural characterization, performed by wide-angle X-ray scattering (WAXS) and small-angle X-ray scattering experiments, revealed unexpected results depending on composition. On the one hand, the poly(hexamethylene carbonate) (PHC)- and POC-rich copolymers crystallize in PHC- and POC-type crystals, as expected. Moreover, upon cooling and heating, in situ WAXS experiments evidenced that these materials undergo reversible solid-solid transitions [δ-α (PHC) and δ-α-ß (POC)] present in the parent components but at lower temperatures. On the other hand, a novel behavior was found for copolymers with 33-73 mol % POC (including the pseudoeutectic point), which are those with higher crystallinities than the parent components. For these copolymers, a new crystalline phase that is different from that of both homopolymers was observed. The in situ WAXS results for these copolymers confirmed that this novel phase is stable upon cooling and heating and does not show any crystallographic feature of the parent components or their solid-solid transitions. FTIR experiments confirmed this behavior, revealing that the new phase adopts a polyethylene-like chain conformation that differs from the trans-dominant ones exhibited by the parent components. This finding challenges the established concepts of isodimorphism and questions whether a combination of crystallization modes (isodimorphism and isomorphism) is possible in the same family of random copolymers just by changing the composition.

Hydrophobic Modification of Poly(γ-glutamic acid) by Grafting 4-Phenyl-butyl Side Groups for the Encapsulation and Release of Doxorubicin.

The delivery of drugs is a great challenge, since most of active pharmaceutical ingredients developed today are hydrophobic and poorly water soluble. From this perspective, drug encapsulation on biodegradable and biocompatible polymers can surpass this problem. Poly(γ-glutamic acid) (PGGA), a bioedible and biocompatible polymer has been chosen for this purpose. Carboxylic side groups of PGGA have been partially esterified with 4-phenyl-butyl bromide, producing a series of aliphatic-aromatic ester derivatives with different hydrophilic-lipophilic balances. Using nanoprecipitation or emulsion/evaporation methods, these copolymers were self-assembled in a water solution, forming nanoparticles with average diameters between 89 and 374 nm and zeta potential values between -13.1 and -49.5 mV. The hydrophobic core containing 4-phenyl-butyl side groups was used for the encapsulation of an anticancer drug, such as Doxorubicin (DOX). The highest encapsulation efficiency was reached for a copolymer derived from PGGA, with a 46 mol% degree of esterification. Drug release studies carried out for 5 days at different pHs (4.2 and 7.4) indicated that DOX was released faster at pH 4.2, revealing the potential of these nanoparticles as chemotherapy agents.

Poly(butylene succinate-co-ε-caprolactone) Copolyesters: Enzymatic Synthesis in Bulk and Thermal Properties.

This work explores for the first time the enzymatic synthesis of poly(butylene-co-ε-caprolactone) (PBSCL) copolyesters in bulk using commercially available monomers (dimethyl succinate (DMS), 1,4-butanediol (BD), and ε-caprolactone (CL)). A preliminary kinetic study was carried out which demonstrated the higher reactivity of DMS over CL in the condensation/ring opening polymerization reaction, catalyzed by Candida antarctica lipase B. PBSCL copolyesters were obtained with high molecular weights and a random microstructure, as determined by 13C NMR. They were thermally stable up to 300 °C, with thermal stability increasing with the content of CL in the copolyester. All of them were semicrystalline, with melting temperatures and enthalpies decreasing up to the eutectic point observed at intermediate compositions, and glass transition temperatures decreasing with the content of CL in the copolyester. The use of CALB provided copolyesters free from toxic metallic catalyst, which is very useful if the polymer is intended to be used for biomedical applications.

Copolymacrolactones Grafted with l-Glutamic Acid: Synthesis, Structure, and Nanocarrier Properties.

The enzymatic ring-opening copolymerization (eROP) of globalide (Gl) and pentadecalactone (PDL) was performed in solution from mixtures of the two macrolactones at ratios covering the whole range of comonomeric compositions. The resulting P(Glx-r-PDLy) random copolyesters were aminofunctionalized by thiol-ene reaction with aminoethanethiol. ROP of γ-benzyl-l-glutamate N-carboxyanhydride initiated by P(Glx-r-PDLy)-NH2 provided neutral poly(γ-benzyl-l-glutamate)-grafted copolyesters, which were converted by hydrolysis into negatively charged hybrid copolymers. Both water-soluble and nonsoluble copolymers were produced depending on copolymer charge and their grafting degree, and their capacity for self-assembling in nano-objects were comparatively examined. The emulsion solvent-evaporation technique applied to the chloroform-soluble copolymers grafted with benzyl glutamate rendered well-delineated spherical nanoparticles with an average diameter of 200-300 nm. Conversely, micellar solutions in water were produced from copolyesters bearing grafted chains composed of at least 10 units of glutamic acid in the free form. The copolymer micelles were shown to be able to load doxorubicin (DOX) efficiently through electrostatic interactions and also to release the drug at a rate that was markedly pH dependent.

Controlling the Isothermal Crystallization of Isodimorphic PBS-ran-PCL Random Copolymers by Varying Composition and Supercooling.

In this work, we study for the first time, the isothermal crystallization behavior of isodimorphic random poly(butylene succinate)-ran-poly(ε-caprolactone) copolyesters, PBS-ran-PCL, previously synthesized by us. We perform nucleation and spherulitic growth kinetics by polarized light optical microscopy (PLOM) and overall isothermal crystallization kinetics by differential scanning calorimetry (DSC). Selected samples were also studied by real-time wide angle X-ray diffraction (WAXS). Under isothermal conditions, only the PBS-rich phase or the PCL-rich phase could crystallize as long as the composition was away from the pseudo-eutectic point. In comparison with the parent homopolymers, as comonomer content increased, both PBS-rich and PCL-rich phases nucleated much faster, but their spherulitic growth rates were much slower. Therefore, the overall crystallization kinetics was a strong function of composition and supercooling. The only copolymer with the eutectic composition exhibited a remarkable behavior. By tuning the crystallization temperature, this copolyester could form either a single crystalline phase or both phases, with remarkably different thermal properties.

Poly (α-Dodecyl γ-Glutamate) (PAAG-12) and Polylactic Acid Films Charged with α-Tocopherol and Their Antioxidant Capacity in Food Models.

Poly (α-dodecyl γ-glutamate) (PAAG-12) was successfully synthesized from poly(γ-glutamic acid) (PGGA) according to Nuclear Magnetic Resonance (NMR) analyses. PAAG-12 films were prepared and enriched with 5% α-tocopherol, with the aim of using them as novel antioxidant active packaging for food applications. Thermogravimetric Analysis (TGA) characterization determined that α-tocopherol improved thermal stability of films, which is beneficial for industrial processing. Polylactic Acid (PLA) films prepared with the same amount of α-tocopherol were used to set a comparative frame and both types of films were applied to two different food models to assess their protective action against oxidation. Water, 50% ethanol (EtOH) and 95% EtOH were used as food simulants and HPLC analyses were performed to determine diffusion and partition coefficients in PLA and the novel polymer, the latter exhibiting slower release rates. Primary oxidation was measured with peroxide value, which revealed that PAAG-12 films with α-tocopherol protected oil-in-water (O/W) emulsions up to 29 days, complying with the Codex Alimentarius.

Comblike Ionic Complexes of Hyaluronic Acid and Alkanoylcholine Surfactants as a Platform for Drug Delivery Systems.

Nontoxic alkanoylcholine soaps ( nACh) were synthesized from choline and fatty acids with numbers of carbons n equal to 12, 14, 16, and 18, the latter including both saturated and 9- cis unsaturated alkanoyl chains. Coupling of nACh with hyaluronic acid (HyA) rendered comblike ionic complexes nACh·HyA that were non-water-soluble. The complexes were thermally stable up to temperatures above 200 °C but readily degraded by water, in particular when hyaluronidases were present in the aqueous medium. In the solid state, these complexes were self-assembled in a biphasic layered structure in which the surfactant and the polysaccharide phases were alternating regularly with a periodicity dependent on the length of the alkanoyl chain. The paraffinic phase was found to be crystallized in saturated complexes with n ≥ 14, but only 18ACh·HyA showed reversible melting crystallization when subjected to cyclic heating-cooling treatment. Nanoparticles with diameters in the 50-150 nm range were prepared by ionotropic gelation from unbalanced 18ACh·HyA complexes with surfactant:HyA ratios of 0.5 and 0.25. These nanoparticles were also structured in layers, swelled slowly in water, and shown to be noncytotoxic in in vitro assays against macrophages cells. It was also shown that the anticancer drug doxorubicin was efficiently encapsulated in both films and NPs of 18ACh·HyA, and its release was shown to be almost linear and complete after one day of incubation in physiological medium. The nACh·HyA complexes constitute a highly promising biocompatible/biodegradable platform for the design of systems suitable for drug transport and targeting delivery in anticancer chemotherapy.

Partially Renewable Poly(butylene 2,5-furandicarboxylate-co-isophthalate) Copolyesters Obtained by ROP.

Cyclic butylene furandicarboxylate (c(BF)n) and butylene isophthalate (c(BI)n) oligomers obtained by high dilution condensation reaction were polymerized in bulk at 200 °C with Sn(Oct)2 catalyst via ring opening polymerization to give homopolyesters and copolyesters (coPBFxIy) with weight average molar masses in the 60,000⁻70,000 g·mol-1 range and dispersities between 1.3 and 1.9. The composition of the copolyesters as determined by NMR was practically the same as that of the feed, and they all showed an almost random microstructure. The copolyesters were thermally stable up to 300 °C and crystalline for all compositions, and have Tg in the 40⁻20 °C range with values decreasing almost linearly with their content in isophthalate units in the copolyester. Both melting temperature and enthalpy of the copolyesters decreased as the content in butylene isophthalate units increased up to a composition 30/70 (BF/BI), at which the triclinic crystal phase made exclusively of butylene furanoate units changed to the crystal structure of PBI. The partial replacement of furanoate by isophthalate units decreased substantially the crystallizability of PBF.

Crystalline structure and thermotropic behavior of alkyltrimethylphosphonium amphiphiles.

Quaternary organophosphonium salts bearing long alkyl chains are cationic surfactants of interest owing to their physical and biological properties. In the present work, the crystal structure and thermotropic behavior of the homologous series of alkyltrimethylphosphonium bromides (nATMP·Br), with the alkyl chain containing an even number (n) of carbon atoms from 12 to 22, have been examined within the 0-300 °C range of temperatures. These compounds were shown to be resistant to heat up to ∼390 °C. The phases adopted at different temperatures were detected by DSC, and the structural changes involved in the phase transitions have been characterized by simultaneous WAXS and SAXS carried out in real-time, and by polarizing optical microscopy as well. Three or four phases were identified for n = 12 and 14 or n ≥ 16, respectively, in agreement with the heat exchange peaks observed by DSC. The phase existing at room temperature (Ph-I) was found to be fully crystalline and its crystal lattice was determined by single-crystal X-ray diffraction methods. Ph-II consisted of a semicrystalline structure that can be categorized as Smectic-B with the crystallized ionic pairs hexagonally arranged in layers and the molten alkyl chain confined in the interlayer space. Ph-II of 12ATMP·Br and 14ATMP·Br directly isotropicized upon heating at ∼220 °C, whereas for n ≥ 16, it converted into a Smectic-A phase (Ph-III) that needed to be heated above ∼240 °C to become isotropic (Ph-Is). The correlation existing between the thermal behavior, phase structure and length of the alkyl side chain has been demonstrated.

Sugar-based bicyclic monomers for aliphatic polyesters: a comparative appraisal of acetalized alditols and isosorbide.

Three series of polyalkanoates (adipates, suberates and sebacates) were synthesized using as monomers three sugar-based bicyclic diols derived from D-glucose (Glux-diol and isosorbide) and D-mannose (Manx-diol). Polycondensations were conducted in the melt applying similar reaction conditions for all cases. The aim was to compare the three bicyclic diols regarding their suitability to render aliphatic polyesters with enhanced thermal and mechanical properties. The ensuing polyesters had molecular weights (Mw) in the 25,000-50,000 g mol-1 range with highest values being attained for Glux-diol. All the polyesters started to decompose above 300 °C and most of them did not display perceivable crystallinity. On the contrary, they had glass transition temperatures much higher than usually found in homologous polyesters made of alkanediols, and showed a stress-strain behavior consistent with their Tg values. Glux-diol was particularly effective in increasing the Tg and to render therefore polyesters with high elastic modulus and considerable mechanical strength.

Modulating the Tg of Poly(alkylene succinate)s by Inserting Bio-Based Aromatic Units via Ring-Opening Copolymerization.

Two series of aliphatic-aromatic copolyesters derived from succinic and 2,5-furandicarboxylic acids, and di-O-2-(hydroxyethyl) resorcinol as diol substituent of either 1,4-butanediol or ethylene glycol, respectively, were obtained by ring opening polymerization(ROP) performed in bulk and catalyzed by Sn(Oct)2. Cyclic oligomers of furandicarboxylate of di-O-2-(hydroxyethyl) resorcinol were successfully synthesized by high-dilution condensation, and then copolymerized with cyclic oligomers of either butylene or ethylene succinate. The synthesized resorcinol-containing succinate-furanoatecopolyesters had Mw oscillating between 50,000 and 30,000 g·mol-1 depending on composition, and they all displayed a nearly random microstructure. They showed an excellent thermal stability with onset decomposition temperatures near 300 °C. They are amorphous with Tg increasing monotonically with the content in resorcinol in both series with values ranging from -30 or -13 °C for butylene and ethylene-based copolyesters, respectively, up to around 45 °C. The resorcinol-containing succinate-furanoate copolyesters showed appreciable hydrolytic degradation when incubated for a few weeks in water under physiological conditions, a behavior that was notably enhanced in the presence of lipases.

Green and selective polycondensation methods toward linear sorbitol-based polyesters: enzymatic versus organic and metal-based catalysis.

Renewable polyesters derived from a sugar alcohol (i.e., sorbitol) were synthesized by solvent-free polycondensation. The aim was to prepare linear polyesters with pendant hydroxyl groups along the polymer backbone. The performance of the sustainable biocatalyst SPRIN liposorb CALB [an immobilized form of Candida antarctica lipase B (CALB); SPRIN technologies] and the organo-base catalyst 1,5,7-triazabicyclo[4,4,0]dec-5-ene (TBD) were compared with two metal-based catalysts: dibutyl tin oxide (DBTO) and scandium trifluoromethanesulfonate [also known as scandium triflate, Sc(OTf)3 ]. For the four catalytic systems, the efficiency and selectivity for the incorporation of sorbitol were studied, mainly using (13) C and (31) P NMR spectroscopies, whereas side reactions, such as ether formation and dehydration of sorbitol, were evaluated using MALDI-TOF-MS. Especially the biocatalyst SPRIN liposorb CALB succeeded in incorporating sorbitol in a selective way without side reactions, leading to close-to-linear polyesters. By using a renewable hydroxyl-reactive curing agent based on l-lysine, transparent and glossy poly(ester urethane) networks were successfully synthesized offering a tangible example of bio-based coatings.

Copolyesters made from 1,4-butanediol, sebacic acid, and D-glucose by melt and enzymatic polycondensation.

Biotechnologically accessible 1,4-butanediol and vegetal oil-based diethyl sebacate were copolymerized with bicyclic acetalized D-glucose derivatives (Glux) by polycondensation both in the melt at high temperature and in solution at mild temperature mediated by polymer-supported Candida antarctica lipase B (CALB). Two series of random copolyesters (PB(x)Glux(y)Seb and PBSeb(x)Glux(y)) were prepared differing in which d-glucose derivative (Glux diol or Glux diester) was used as comonomer. The three parent homopolyesters PBSeb, PBGlux, and PGluxSeb were prepared as well. Both methods were found to be effective for polymerization although significant higher molecular weights were achieved by melt polycondensation. The thermal properties displayed by the copolyesters were largely dependent on composition and also on the functionality of the replacing Glux unit. The thermal stability of PBSeb was retained or even slightly increased after copolymerization with Glux, whereas crystallinity and melting temperature were largely depressed. On the contrary, the glass-transition temperature noticeably increased with the content in Glux units. PGluxSeb distinguished in displaying both T(g) and T(m) higher than PBSeb because a different crystal structure is adopted by this homopolyester. The hydrolytic degradability of PBSeb in water was enhanced by copolymerization, in particular, when biodegradation was assisted by lipases.

Nanoparticles of esterified polymalic acid for controlled anticancer drug release.

Esterification of microbial poly(malic acid) is performed with either ethanol or 1-butanol to obtain polymalate conjugates capable to form nanoparticles (100-350 nm). Degradation under physiological conditions takes place with release of malic acid and the corresponding alcohol as unique degradation products. The anticancer drugs Temozolomide and Doxorubicin are encapsulated in nanoparticles with efficiency of 17 and 37%, respectively. In vitro drug release assays show that Temozolomide is almost completely discharged in a few hours whereas Doxorubicin is steadily released along several days. Drug-loaded nano-particles show remarkable effectiveness against cancer cells. Partially ethylated poly(malic acid) nano-particles are those showing the highest cellular uptake.

Complexes of polyglutamic acid and long-chain alkanoylcholines: nanoparticle formation and drug release.

Ionic complexes of microbial poly(γ-glutamic acid) and alkanoylcholines are fully bio-based comb-like systems able to self-organize in an ordered amphiphilic structure made of hydrophobic and hydrophilic alternating layers. Incubation of complex films under physiological conditions for one month promoted dissociation of the complex and hydrolysis of the choline ester without almost degradation of polyglutamic acid. Complex decomposition rates were depending on alkanoyl chain length and on complex stoichiometry as well. Nanoparticles with 50-100 nm diameter were successfully prepared from the stearoylcholine complex with a surfactant to polymer ratio of 0.75 and loaded with theophylline, carbamazepine or doxorubicin drugs. The releasing of the drugs from nanoparticles took place upon incubation at very different rates depending on the drug. Theophylline and carbamazepine were discharged in hours whereas doxorubicin was very slowly delivered along months. The observed differences were related to the different interaction mechanism operating between the drug and the complex.

High T(g) bio-based aliphatic polyesters from bicyclic D-mannitol.

The carbohydrate-based diol 2,4:3,5-di-O-methylene-d-mannitol (Manx) has been used to obtain aliphatic polyesters. Manx is a symmetric bicyclic compound consisting of two fused 1,3-dioxane rings and bearing two primary hydroxyl groups. In terms of stiffness, it is comparable to the widely known isosorbide, but it affords the additional advantages of being much more reactive in polycondensation and capable of producing stereoregular polymers with fairly high molecular weights. A fully bio-based homopolyester (PManxS) has been synthesized by polycondensation in the melt from dimethyl succinate and Manx. The high thermal stability of PManxS, its relatively high glass transition temperature (Tg = 68 °C) and elastic modulus, and its enhanced sensitivity to the action of lipases point to PManxS as a polyester of exceptional interest for those applications where biodegradability and molecular stiffness are priority requirements. In addition, random copolyesters (PBxManxyS) covering a broad range of compositions have been obtained using mixtures of Manx and 1,4-butanediol in the reaction with dimethyl succinate. All PBxManxyS were semicrystalline and displayed Tg values from -29 to +51 °C steadily increasing with the content in Manx units. The stress-strain behavior of these copolyesters largely depended on their content in Manx and they were enzymatically degraded faster than PBS.

Comb-like ionic complexes of hyaluronic acid with alkyltrimethylammonium surfactants.

Stoichiometric complexes of hyaluronic acid with alkyltrimethylammonium surfactants bearing octadecyl, eicosyl and docosyl groups were prepared by ionic coupling in aqueous solution. The complexes were non soluble in water but soluble in organic solvents. In the solid state they self-assembled in a biphasic layered structure with the alkyl side chains forming a separate phase that melted in the 50-60 °C range. They were stable to heating up to above 200 °C.