Racemic Poly Research Articles

Study of optically active methacrylates containing 1,1′‐binaphthyl side‐groups polymerized by anionic, group transfer and free radical methods

AbstractOptically active and racemic poly(meth)acrylates with pendant 1,1′‐binaphthalene moiety of 2‐methacryloyloxy‐ and 2‐acryloyloxy‐2′‐methoxy‐1,1′‐binaphthalene (MAMBN and AMBN) were synthesized by anionic, group transfer and free radical polymerization methods. Their polymerizability and chiroptical properties are somewhat different, depending on the three types of polymerization methods used. The yields for poly(MAMBN)s are lower than for poly(AMBN)s. The optical rotation of the optically active polymers is identical to that of the corresponding monomers. The values of specific rotation of optically active poly(AMBN)s are much larger than those of optically active poly(MAMBN)s. © 2002 Society of Chemical Industry

Poly(alpha-alkyl gamma-glutamate)s of microbial origin. 2. On the microstructure and crystal structure of poly(alpha-ethyl gamma-glutamate)s.

The stereochemical microstructure and crystalline structure of nearly racemic poly(alpha-ethyl gamma,DL-glutamate) obtained by esterification of biosynthetic poly(gamma-glutamic acid) were examined by NMR, DSC, and powder X-ray diffraction. The two enantiomerically pure poly(alpha-ethyl gamma-glutamate)s, as well as the racemic stereocopolymers with random and alternating microstructure, were prepared by chemical synthesis and studied in parallel to help in the interpretation of the data. The (13)C NMR analysis revealed that biosynthetic poly(alpha-ethyl gamma,DL-glutamate) consists of a block stereocopolymer accompanied by minor amounts of a mixture of the two optically pure homopolymers. The polymer is crystalline, with a degree of crystallinity and crystal structure essentially similar to those displayed by the optically pure polymers but clearly different from the alternating copolymer. Conversely, the racemic stereocopolymer with a random microstructure prepared by chemical synthesis is amorphous. The crystal structure of the racemic mixture of the D- and L-homopolymers seems to be very close to that of the biosynthetic stereocopolymer, although some indications suggesting the existence of a stereocomplex were found.

In vitro delivery of a sparingly water soluble compound from PLA50 microparticles

The administration of a sparingly soluble drug is always problematic, especially when the drug has to be released from the degradable matrix of a polymeric drug delivery system. Attempts were made to achieve the complete release of 1-[2-(fluorobenzoyl) aminoethyl]-4-(7-methoxynaphtyl)piperazine (FAMP), a potential anxiolytic and antidepressor hydrophobic compound, from racemic poly(lactic acid) (PLA50)-based microparticles, 100% release was required at a low rate in order to allow monthly repeated S.C. or I.M. injections of this potent compound. FAMP-polymer combinations were made in the form of microspheres by the solvent evaporation technique. Release profiles were investigated under dynamic conditions by using a constant flow rate of pH 7.4 0.15 M phosphate buffer, used as a model of body fluids. Under these conditions, none of the microsphere compositions led to total release within a month, even when hydrophilic excipients, namely fructose and PEG were added. PLA50-FAMP microparticles with compositions and sizes similar to those of the microspheres, were then made by direct blending in dichloromethane, evaporation of the solvent, grinding and sieving. These formulations also failed in providing total drug release within 30 days, even at a high drug load. FAMP/PLA50/water-soluble additive, ternary grounded particles were finally prepared with fructose, PLA50 oligomers or poly(ethylene glycol) (PEG) as the additive. Only PLA50 grounded particles with percolating FAMP-PEG microdomains allowed 100% release of FAMP over a 30 day period, at a quasi constant rate which depended primarily on solubility and channelling provided the flow was slow enough. Data are discussed in terms of the accessibility of the entrapped drug to the aqueous medium.

Hydrolytic degradability of poly(3-hydroxyoctanoate) and of a poly(3-hydroxyoctanoate)/poly(R,S-lactic acid) blend

Films of bacterial poly(3-hydroxyoctanoate) (PHO) (Mn = 85 000) pure or blended with racemic poly[(R,S)-lactic acid] (PLA50) of low molecular weight (Mn = 1100) were prepared by solvent casting techniques and incubated in buffer solutions at 37°C and at different pH. Changes in weight, molecular weight and morphology were recorded during hydrolysis experiments. The PHO hydrolytic degradation process was very slow: after 5 months of degradation, only 0.1% of ester functions were hydrolyzed. In the case of a PHO/PLA50 blend (8020, w/w), after 1 month, no more PLA50 was present in the film and PHO molecular weight decrease was significantly more important than in the case of pure PHO degradation; the hydrolytic scission of PHO chains was enhanced by the presence of PLA50. Differential scanning calorimetry achieved on PHO/PLA50-blended samples displayed a lack of complete miscibility between both components. In the early stage of ageing, an increase of crystallinity for the different materials was observed in all cases.

Antibiotic-loaded plaster of Paris implants coated with poly lactide-co-glycolide as a controlled release delivery system for the treatment of bone infections.

Plaster of Paris implants containing vancomycin (60 mg/g of carrier) were prepared in order to be used as local delivery system for the treatment of bone infections. The regulation of the release rate was performed by coating the carrier with a polylactide-co-glycolide polymer composed by 10% (w/w) polyglycolic acid and 90% (w/w) racemic poly (D,L-lactic acid). The release of the antibiotic from the biodegradable matrix was evaluated in vitro. From this investigation, it is clear that the drug elution depends on the coating depth. After a burst effect occurring on the first day of the experiment, therapeutic concentrations were measured during one week when uncoated implants were used. The coating allowed decrease of the burst effect and extended efficient release to more than five weeks when the implants were embedded with six layers (162 microns) of PLA45GA10. This delivery system was implanted into the femoral condyle of rabbits. It was shown that the in vivo release was also closely regulated by the coating depth. In all bone tissues (bone marrow and cortical bone) surrounding the pellets, the drug concentration exceeded the Minimum Inhibitory Concentration for the common causative organisms of bone infections (Staphylococcus aureus) for at least four weeks without inducing serum toxic levels. Due to its cheapness, facility of use and sterilization, biocompatibility and biodegradability, plaster of Paris coated with PLA45GA10 polymer giving a controlled release of vancomycin appears to be a promising sustained release delivery system of antibiotics for the treatment of bone and joint infections.

Poly(β-malic acid): obtaining high molecular weights by improvement of the synthesis route

Poly(β-malic acid), PMLA, was first synthesized with the aim of being used as a macromolecular prodrug. However, this biodegradable polymer is now the parent compound of a large family functional polymers, copolymers and polystereoisomers. The requirement for high molecular weight polymers for a series of temporary therapeutic or specific applications needs to be conducted to examine the different steps of the synthesis route starting from either racemic or chiral aspartic acid. Drastic purifications of the intermediate products and of the β-substituted-β-lactone used as monomer has allowed the synthesis of polymers with high molecular weights, in a reproducible manner. In the case of racemic poly(β-malic acid benzyl ester), a precursor of PMLA, it is now possible to prepare polymers with a M SEC superior to 150 000 (polystyrene standards). The specific catalytic hydrogenolysis of the lateral benzyl protecting groups can be carried out and leads to the corresponding PMLA with long molecular chains, which are necessary for certain applications in vivo. The results have been extended to different racemic and optically active derivatives of this poly(3-hydroxy aci) ester type. Consequently, reproducible characteristics of the corresponding polymeric materials can be obtained.

Screening of microorganisms for biodegradation of poly(lactic-acid) and lactic acid-containing polymers.

The ability of some microorganisms to use lactic acid stereocopolymers and copolymers with glycolic acid as sole carbon and energy sources was studied under controlled or natural conditions. First, 14 filamentous fungal strains were tested in liquid cultures, adopting total lactic acid consumption, nitrogen source exhaustion, and maximal biomass production as selection criteria. Two strains of Fusarium moniliforme and one strain of Penicillium roqueforti were able to totally assimilate DL-lactic acid, partially soluble racemic oligomers (MW = 1,000), and the nitrogen source. Only one strain of F. moniliforme was able to grow on a poly(lactic acid)-glycolic acid copolymer (MW = 150,000) after 2 months of incubation at 28 degrees C on synthetic agar medium. Mycelium development was examined by scanning electron microscopy. F. moniliforme filaments were observed to grow not only at the copolymer surface but also through the bulk of the copolymer. In a second approach, plates made of a racemic poly(lactic acid) were buried in the soil before being incubated in petri dishes containing mineral agar medium under controlled conditions. Five strains of different filamentous fungi were isolated, and their ability to assimilate racemic poly(lactic acid) oligomers was tested in liquid cultures.

Enzymatic and Environmental Degradation of Racemic Poly(3-hydroxybutyric acid)s with Different Stereoregularities

Racemic poly(3-hydroxybutyric acid) (P(3HB)) was prepared by the ring-opening polymerization of racemic β-butyrolactone (β-BL) in the presence of methylaluminoxane and fractionated into five components with various isotactic diad fractions ([i]) varying from 0.88 to 0.54. The degree of X-ray crystallinity of isotactic P(3HB) films decreased from 33 to 8% as the [i] value was decreased from 0.88 to 0.54. A predominantly syndiotactic P(3HB) ([i] = 0.30) was prepared by the polymerization of racemic β-BL in the presence of 1-ethoxy-3-chlorotetrabutyldistannoxane, and its crystallinity was 26%. Enzymatic degradation of P(3HB) films with different stereoregularities was carried out at 37 °C in 0.1 M potassium phosphate buffer (pH 7.4) in the presence of PHB depolymerase purified from Alcaligenes faecalis. The highest rate of enzymatic hydrolysis was observed at an [i] value of 0.74. Syndiotactic P(3HB) film was hardly hydrolyzed by the enzyme. The enzymatic degradation products of racemic P(3HB) samples ([i] =...

Single Crystals and Crystalline Morphology of Synthetic Racemic Poly(β-hydroxybutyrate)

Single crystals of synthetic racemic poly(β-hydroxybutyrate), PHB, of varying tacticities were grown in dilute chloroform/ethanol solutions. The single crystals of highly isotactic synthetic PHB were spear or lath shaped, like those of bacterial PHB; those from essentially atactic polymer were wrinkled but displayed the same electron diffractogram as isotactic PHB. Syndiotactic PHB gave a nondiffracting precipitate of two different morphologies; further examination suggests that these morphologies differ in tacticity. The average overall tacticities of the precipitated and soluble material were determined by 13C NMR and found to be unchanged by the precipitation. This provides evidence that some cocrystallization of the R and S repeat units can occur and that the single crystals obtained can be correlated with original sample tacticities.

Single crystals of bacterial and synthetic poly(3-hydroxyvalerate)

Lamellar, folded-chain single crystals of bacterial homopolymer, of synthetic racemic poly(β-hydroxyvalerate) (PHV), and of bacterial poly(β-hydroxybutyrate-co-(β-hydroxyvalerate) (P(HB-co-HV)), with high HV content (superior to 77 mol%) were obtained from dilute ethanolic solutions. They all exhibited the same square shape as opposed to the characteristic lath shape of poly(β-hydroxybutyrate) single crystals and P(HB-co-HV) single crystals with low HV content. The electron diffraction patterns recorded from selected areas of these single crystals were identical and allowed the comparison of our observed basal unit cell parameters with those derived from X-ray fibre diffraction. The results provided a visual and quantitative confirmation of the isodimorphism phenomenon and confirmed the P212121 orthorhombic symmetry. The lower perfection in the morphology of the single crystals from the synthetic PHV homopolymer than in those from the bacterial samples is attributable to a stereoblock segregation during the crystallization according to block chirality.Key words: poly(3-hydroxyvalerate), single crystals, bacterial polyester, electron diffraction, isodimorphism.

Microstructure of Poly[(R,S)-.beta.-hydroxybutyrate] by 13C NMR

High-resolution 13 C NMR spectra were obtained for a wide tacticity range of racemic poly-[(R,S)-β-hydroxybutyrate] samples and interpreted with regard to several statistical models. None of the samples followed Bernoullian statistics, but the syndiotactic and atactic fractions essentially obeyed first-order Markov statistics, as derived for racemic monomer. Fitting to a second-order Markovian model confirmed previously-held theories regarding the blocky nature of the polymer. An enantiomorphic model described the more isotactic samples well but did not adequately describe the atactic and syndiotactic ones ; a two-site model involving enantiomorphic and first-order Markovian sites was therefore proposed, and the parameters necessary to describe each sample were calculated. Average isotactic and syndiotactic block lengths were also calculated and used in the interpretation of degradation and single-crystal results.

Solid state 2H NMR study of racemic poly(γ-benzyl glutamate)

The dynamical stacking structure of the phenyl rings in racemic poly(γ-benzyl glutamate) (PBG) deuterated in benzyl methylene or phenyl ring groups was investigated using solid state 2H NMR quadrupole echo spectroscopy. Line shapes and spin-lattice relaxation times of racemic PBG were compared with those of poly(γ-benzyl l-glutamate) (PBLG). The large amplitude motions along a side chain are rather restricted in the stacked state, while the phenyl rings at the end of the side chain undergo a 180°-flipping motion even in the stacked state as in PBLG. The amplitude of the fast librations in the stacked state is smaller by several degrees than that of PBLG. About 75% of the side chains participate in the stacking for an equi-weight mixture of l- and d-molecules.

Crystalline oligomeric stereocomplex as an intermediate compound in racemic poly(DL‐lactic acid) degradation

AbstractHydrolytic degradation of intrinsically amorphous poly(DL‐lactic acid) was re‐examined in pH 7.4 isoosmolar phosphate buffer at 37°C. Size‐exclusion chromatogarphy, X‐ray scattering and differential scanning calorimetry were used to monitor molecular weight and morphology changes up to the ultimate degradation stage. It was found that heterogeneous degradation of poly(DL‐lactic acid) yielded a crystalline residual material of low molecular weight. Comparison with a stereocomplex made of equimolar poly(L‐lactic acid) and poly(D‐lactic acid) showed that the poly(DL‐lactic acid) degradation residue was actually an oligomeric stereocomplex. The formation of stereoregular oligomeric enantiomers agreed well with the predominantly isotactic structure of poly(DL‐lactic acid) obtained by ring‐opening polymerization of DL‐lactide and argued in favour of the stereodependence of main chain ester bond cleavage.

Side Chain Motion and Structure of Racemic Poly(γ-benzyl glutamate) as Studied by Solid State High-Resolution 13C Nuclear Magnetic Resonance

The side chain motion and structure of the racemic mixture of poly(γ-benzyl glutamate) (PBDLG) in the solid state were studied by means of the cross polarization/magic angle spinning (CP/MAS) 13C NMR. Cβ and Cγ regions of NMR spectra for PBDLG in the stacked state of phenyl rings exhibit a remarkable difference from those for poly(γ-benzyl L-glutamate) (PBLG) with no side chain stacking. Use of γ-d2 PBDLG, deuterated at Cγ, showed that the upfield shift occurs in a part of γ-carbons. It was suggested that this new peak arises from the regular side chain conformation with phenyl ring stacking. The measurements of 13C T1ρ, spin-lattice relaxation time in the rotating frame, indicated that both the side chain and main chain motions are restricted in the stacked state. However, it is noticeable that such effect of stacking is especially remarkable for Cγ rather than phenyl ring. This means that phenyl rings have a rather high mobility even in the staked state.

Biodistribution of trans-1,2-diammocyclohexane-trimellitato-platinum(II) attached to macromolecular carriers I. Poly(hydroxyethyl-d,l-asparagine) carrier

Two types of macromolecular drug forms of the second generation piatinum antitumor drug 4-carboxy-phtalato-(trans, 1,2-diaminocyclohexane)platinum(II) (TMA) were prepared with non-biodegradable carriers derived from racemic poly (N 4 -substituted aspartamide): AN type was prepared from N-(2-hydroxyethyl) and AR type from N-(2-hydroxypropyl) derivative by acylation with trimellitato residues, thus yielding primary and secondary ester honds respectively. Plasma levels, urinary excretion and organ deposition of platinum were followed after administration into rats. When compared with free TMA both types of macromolecular forms showed a retardation effect in platinum pharma-cokinetics with the most pronounced differences using the AR type. Considering all possible biodegradable bonds in the polymeric drug forms the nature of the drug-polymer link seemed to play an important role in the kinetics of drug release as revealed by the differences between the AN and AR type.

Synthesis and polymerization of racemic and optically active substituted ß‐propiolactones. V. α‐methyl ß‐propiolactone

AbstractR(+) and S(−) enantiomers of α‐methyl β‐propiolactone (MPL) have been synthesized from the corresponding α‐methyl β‐hydroxymethylpropionates and racemic MPL from methyl methacrylate. The optical purity and absolute configuration of these lactones were determined using 1H‐NMR spectroscopy after complexation with a chiral compound: 2,2,2‐trifluoro‐1‐(9‐anthryl)‐ethanol. Optical purities of 100% were obtained for both the S(−) ([α0] = −10.4°, c = 1.3 g/dL in CHCl3) and the R(+) ([α0] = +10.5°, c = 1.0 g/dL in CHCl3) enantiomers. The corresponding racemic and optically active polylactones [poly(MPL)] were prepared by anionic polymerization, in bulk and in solution, as well as poly(MPL)s of intermediate optical purities. The polymers thus obtained are optically active ([α0] = 16.2° in CHCl3 for the optically pure polymer, S configuration) and exhibit significant differences. For example, the racemic poly(MPL) is soluble in several organic solvents such as tetrahydrofuran, benzene, CCl4, CH2Cl2, hexafluoroisopropanol, and CHCl3, whereas the optically active poly(MPL)s are soluble in CHCl3 and hexafluoroisopropanol only. Moreover, racemic poly(MPL) is amorphous whereas optically active poly(MPL)s are semicrystalline for optical purities larger than 51%. Melting temperatures and enthalpies of fusion of the semicrystalline polylactones vary with optical purity whereas glass transition temperatures remain invariant for all polymers, at about −28°C. The poly(MPL) of highest optical purity exhibits a melting temperature of 95°C and an enthalpy of fusion of 61 J/g.

Luminescence spectroscopy as a probe of binding state differences between enantiomeric and racemic poly(pyridyl)-ruthenium(II) chelates intercalated in smectite clays

Luminescence spectral studies (steady state and dynamic) indicate clear differences between the binding states of enantiomeric and racemic forms of poly(pyridyl)-ruthenium(II) complexes intercalated in Na-hectorite clay, even at low loadings of the exchanging sites.

A rheo‐optical study on the reformation of structure in racemic poly(γ‐benzyl glutamate) liquid crystals

AbstractTransmitted light intensities were measured by means of the polarized light technique for the nematic liquid crystal phase of racemic poly(γ‐benzyl glutamate) (PBG) in m‐cresol at 25°C after cessation of steady flow at shear rates ranging from 0.2 to 110 s−1. Weight‐average molecular weights of PBG used were 1.5, 2.1, and 2.6 × 105, while the concentrations varied between 20, 30, and 40 wt percent. Transmitted light intensities with crossed and parallel polarizers, Ix and I|, show wavy changes with time after cessation of steady flow, indicating the retardation decreases with time. An attempt was made to explain experimental results on the basis of a simple model, in which not only relaxation of molecular orientation but also effects of the wall and disclination were taken into account.

Studies on the Formation of Regular Stacks of Benzyl Groups in Racemic Poly(γ-benzyl glutamate) Films

Studies on the Formation of Regular Stacks of Benzyl Groups in Racemic Poly(γ-benzyl glutamate) Films

Polymerization of α,α‐disubstituted‐β‐propiolactones and lactams. 10. Crystalline structure, thermal and mechanical studies of statistical and block copolymers of pivalolactone and α‐methyl‐α‐propyl‐β‐propiolactone

AbstractAB and ABA block copolyesters based on racemic poly(α‐methyl‐α‐n propyl‐α‐propiolactone) (PMPPL) as a “soft” or elastomeric segment and polypivalolactone (PPL) as a “hard” or crystallizable segment have been synthesized and compared with random copolymers of the same composition. X‐ray studies show the coexistence of polymorphic crystal forms for a given polymer in a given sample. Thermal and dynamic mechanical properties give clear evidence of heterophase structure corresponding to segregation of PPL and PMPPL. The crystalline phase clearly provides thermally reversible crosslinking in the ABA block copolymers. On stretching, the planar zigzag form of PMPPL is observed. Because of the domain structure, moduli of ABA samples are higher than those of PMPPL and their tensile strengths are similar to those of comparable styrene‐butadiene block copolymers.The polymer synthesis was achieved by sequential monomer addition with tetrahexyl ammonium benzoate as initiator. For the ABA polymers the diammonium salt of sebacic acid provided a di‐functional initiator. The agreement between calculated and observed molecular weights testify to the “living” character of this polymerization reaction.