Jean Coudane

More about the polymerization of lactides in the presence of stannous octoate

The ring-opening polymerization of lactide cyclic monomers in the bulk in the presence of tin(II) 2-ethylhexanoate (stannous octoate or SnOct2) was reexamined under conditions allowing for the end group characterization of growing chains by high-resolution 1H-NMR. Data collected for low values of the monomer/initiator (M/I) ratio showed that the DL-lactide ring was opened to yield lactyl octoate-terminated short chains. A cationic-type mechanism involving co-initiation by octanoic acid was proposed to account for experimental findings. The formation of a side product, hydroxytin(II) lactate (HTL), was found which appeared able to initiate lactide polymerization and to yield a high molecular weight PLA50 polymer. However the polymerization with stannous octoate was faster than the HTL one. Anyhow, data suggested that both SnOct2 and HTL are likely to act simultaneously as initiators during the polymerization of lactides in the presence of SnOct2. A complete reaction scheme was proposed to account for the presence of the various compounds likely to be formed under these conditions.

Something new in the field of PLA/GA bioresorbable polymers?

Polymers issued from glycolic acid and lactic acids (PLAGA) are now used worldwide as bioresorbable devices in surgery and in pharmacology. Their abiotic hydrolytic degradation has been shown to depend on diffusion-reaction phenomena and to proceed homogeneously or heterogeneously, depending on many factors. Two initiators are presently used industrially to make PLAGA polymers by ring opening polymerisation of lactide and/or glycolide in the bulk, namely Sn octanoate and zinc metal. In this contribution, attention is paid to the differences generated by the use of these two initiator systems in the case of the polymerisation of DL-lactide. Various poly(DL-lactide)s were prepared and characterised by size-exclusion chromatography (SEC), differential scanning calorimetry (DSC) and nuclear magnetic resonance spectroscopy (NMR). These polymers were allowed to age in pH=7.4 isoosmolar phosphate buffer at 37 degrees C. Under these conditions, polymers prepared by the two initiator systems showed dramatic differences when the fates of parallel sided specimens of rather large dimensions were considered. These differences were related to the esterification of some of the OH chain ends by octanoic acid and to the presence of rather hydrophobic low molecular weight by-products which were insoluble in the solvent generally used to purify the crude PLAGA polymers. These new findings should be of great interest in the case of PLAGA based matrices aimed at drug delivery.

More about the stereodependence of DD and LL pair linkages during the ring‐opening polymerization of racemic lactide

For the last two decades, mixtures of D- and L-lactides, the DD and LL cyclic dimers of lactic acid enantiomers, were polymerized under various conditions of temperature, time, and initiators. Consequences of the dimeric structure of lactide molecules on the distribution of chiral units and on the properties of resulting PLAs were discussed occasionally. In the meantime, NMR techniques have grown up and are now powerful tools to investigate configurational structures from stereosensitive resonances. Thus far, correlation between experimental data and theoretical n-ades were based on Bernoullian-type enchainments of DD and LL pairs of lactyl units present in PLA stereocopolymer chains obtained by ring-opening polymerization. Analysis of NMR spectra of racemic PLAs of different origins, including literature data, was reconsidered on the basis of the probabilities to form iso- and hetero-dyads during chain propagation. Consideration of equireactivity and stereodependent reactivity between the DD and LL pairs generated from a racemic mixture of D- and L-lactide diastereoisomers led us to the conclusion that DD/LL and LL/DD heterotactic junctions are preferentially formed when one uses Sn octoate and Zn metal as initiator systems, even though completed macromolecules remain predominantly isotactic because of the isodyads inherently present in lactide diastereoisomers. A simple method is proposed to determine whether homo- or cross-addition of DD and LL pairs is favorized in any poly(racemic lactide) in the absence of transesterification rearrangements. This method is based on the comparison of experimental relative weights of the three distinct groups of resonances due to carbonyl carbon atoms with relative weights calculated according to the Bernoullian statistics. It allows the determination of a coefficient of stereoselectivity Pi from which one can easily evaluate the average length of isotactic blocks Li without any computation approximations.

Ring opening polymerization of D,L-lactide in the presence of zinc metal and zinc lactate

The polymerization of D,L-lactide in the presence of zinc metal was investigated for low values of the monomer/catalyst ratio in order to allow end-group characterization of the growing chains by high resolution 360MHz 1H NMR. The results showed that the polymerization was moisture sensitive and that only a fraction of zinc was active. Small quantities of a side-product were detected and identified as zinc lactate. This compound appeared to be an efficient initiator of the ring-opening polymerization in the bulk. Zinc lactate is thus proposed as the actual initiator of the polymerization of 1,4-dioxane-2,5-diones in the presence of zinc metal. A polymerization mechanism based on a cationic process co-catalysed by lactic acid is also proposed, which accounted very satisfactorily for experimental data. Initiation by zinc lactate yielded high molecular weight polymers with a high degree of conversion and rather high polymerization rates. Therefore, zinc lactate appears to be an attractive alternative to the initiations by zinc metal and stannous octoate, the latter being suspected of some toxicity.

Stannous octoate-versus zinc-initiated polymerization of racemic lactide

SummaryRacemic lactide (D,L-lactide) was bulk-polymerized comparatively using stannous octoate and zinc metal as initiators. A two-level fractional factorial design was used to assess the influence of selected experimental variables with respect to intermolecular transesterification, whose extent in the resulting high molecular weight poly(D,L-lactide)s (PLA50) was investigated by13C NMR. Five variables, namely polymerization temperature, monomer-to-initiator ratio, polymerization time, nature of the initiator and monomer degassing-time, were found significant and were ranked according to their average effect on transesterification. A significant interaction of polymerization temperature and polymerization time was also detected. Zinc led to lower stereoregularity than stannous octoate.

Preparation and degradation of surfactant-free PLAGA microspheres

Abstract PLA oligomers which have an amphiphilic surfactant-like structure with a polar head and a long hydrophobic tail were used to prepare self-stabilized microparticles of the PLAGA-type by the evaporation solvent method. It is shown that PLA50 oligomers prepared by polycondensation of dl -lactic acid were able to emulsify an organic solution of high molecular weight PLA37.5GA25 (37.5% L-LA, 37.5% D-LA and 25% GA units) in salt-containing aqueous media. Resulting microspheres were characterized by SEC, DSC, SEM and by size measurements. In vitro degradation was investigated. The mechanism of degradation is driven by the rapid release of oligomeric materials. However, the degradation rate of the high molecular weight components of the matrix was not greatly affected by the short-term presence of the oligomeric materials introduced as matrix-like surfactant. As an example, surfactant-free progesterone-containing microspheres were prepared by the solvent evaporation method.

Zn lactate as initiator of dl-lactide ring opening polymerization and comparison with Sn octoate

SummaryZn lactate, 3H2O and dehydrated Zn lactate were used as initiator to polymerize DL-lactide under various conditions. It is shown that the latter does polymerize DL-lactide up to high molecular weight at a slower rate than Sn octoate. Zn lactate being formed when lactic acid is allowed to react with Zn metal, it is believed that the active species in Zn metal initiation is Zn lactate. Comparison was made of the two poly(DL-lactide) initiated with Zn metal and Sn octoate respectively and selected to have almost similar characteristics. It is shown that degradation characteristics of the two polymers are different, especially water uptake and rate of heterogeneous degradation. It is further shown that residual Sn concentrated within the matrix remnants whereas the content in Zn remained constant according to degradation controlled release.

Influence of polymerization conditions on the hydrolytic degradation of poly(DL-lactide) polymerized in the presence of stannous octoate or zinc-metal.

Laboratory- and pilot-scale racemic polylactides (PLA50) were synthesized in the presence of stannous octoate (SnOct2) or zinc-metal as initiators in the absence of alcohol. The resulting polymers were processed by compression molding or injection molding depending on the batch scale. The hydrolytic degradation of compression-molded samples selected to be comparable was investigated first in order to show the influence of the initiator system. Differences in water uptake were found between PLA50-Zn (zinc-metal initiation) and PLA50-Sn (SnOct2 initiation). PLA50-Zn being much more hydrophilic. PLA50-Sn exhibited a slower molecular weight decrease and delayed onsets of weight loss, release of acidity and stereocomplex formation, with respect to PLA-Zn. The concentration in residual tin in PLA50-Sn increased from 306 to 795 ppm during aging. In the case of PLA50-Zn the residual metal remains constant at ca. 40 ppm. In a second series of experiments, high molecular weight PLA50 different in characteristics and in initiator, synthesized under pilot-scale, were compared. The effects of the initiator on the degradation of the polymers well agreed with laboratory-scale findings, differences in hydrophobicity being enlarged by the up scaling. PLA50-Sn polymers appeared much more degradation resistant than PLA50-Zn ones. Contributions of the other characteristics (e.g. molecular weight, purity, stereoregularity, processing) were shown to be important as well.

Well-defined PCL-graft-PDMAEMA prepared by ring-opening polymerisation and click chemistry

Amphiphilic and cationic PCL-based degradable polyester was synthesized by copper-catalyzed azide-alkyne cycloaddition (CuAAC).

Effect of various additives and polymers on lysozyme release from PLGA microspheres prepared by an s/o/w emulsion technique.

Incomplete protein release from PLGA-based microspheres due to protein interactions with the polymer is one of the main issues in the development of PLGA protein-loaded microspheres. In this study, a two-dimensional adsorption model was designed to rapidly assess the anti-adsorption effect of formulation components (additives, additives blended with the polymer or modified polymers). Lysozyme was chosen as a model protein because of its strong, non-specific adsorption on the PLGA surface. This study showed that PEGs, poloxamer 188 and BSA totally inhibited protein adsorption onto the PLGA37.5/25 layer. Similarly, it was emphasised that more hydrophilic polymers were less prone to protein adsorption. The correlation between this model and the in vitro release profile was made by microencapsulating lysozyme with a low loading in the presence of these excipients by a non-denaturing s/o/w encapsulation technique. The precipitation of lysozyme with the amphiphilic poloxamer 188 prior to encapsulation exhibited continuous release of active lysozyme over 3 weeks without any burst effect. To promote lysozyme release in the latter stage of release, a PLGA-PEG-PLGA tribloc copolymer was used; lysozyme was continuously released over 45 days in a biologically active form.