ABSTRACT:The chemical composition and quantitative molar ratios among all components of biodegradable polyphosphoester copolymers of dl-lactide and ethylphosphate were determined by a comprehensive set of NMR spectroscopic methods. The polyphosphoester copolymers studied were synthesized using condensation polymerization of oligomeric dl-lactide prepolymers and ethyl dichlorophosphate. Conclusive identification of the chemical shift patterns of all functional groups in the copolymers required additional NMR methods such as 31 P-NMR and two-dimensional 1 H-1 H COSY NMR, in addition to the synthesis and comparative NMR analysis of model compounds possessing identical phosphoester linkages in the polyphosphoester copolymers. For the polymers synthesized using the bulk polycondensation process, 1 H-1 H COSY NMR analysis revealed the presence of a small amount of side products that were undetected by 1 H-NMR alone. These side reactions most likely occurred between the pendant ethoxy group of the phosphoesters and the hydrogen chloride gas generated in the bulk polycondensation process.31 P-NMR spectra of the copolymers revealed a consistent triple-peak pattern characteristic of phosphoesters linked to a racemic mixture of d,l-lactides. These results offered new insight into the side reactions occurring in bulk polymerization of polyphosphoesters and provided a powerful tool of characterizing complex biodegradable polymers.
Poly(lactide-co-ethylphosphate)s, a new class of linear phosphorus-containing copolymers made by chain-extending low-molecular-weight polylactide prepolymers with ethyl dichlorophosphate, were investigated for their in vitro and in vivo degradation mechanism and kinetics. Microspheres made from poly(lactide-co-ethylphosphate) were studied under both accelerated and normal in vitro degradation conditions. Gel permeation chromatography (GPC), 1H- and 31P-NMR, weight loss measurements, and differential scanning calorimetry (DSC) techniques were used to characterize the change of molecular weight (M(w)), chemical composition, and glass transition temperature (T(g)) of the degrading polymers. The results indicated that the copolymers degraded in a two-stage fashion, with cleavage of the phosphate-lactide linkages contributing mostly to the initial more rapid degradation phase and cleavage of the lactide-lactide bonds being responsible for the slower latter stage degradation. The decrease in the copolymer M(w) was accompanied by a continuous mass loss. Results from the accelerated degradation studies confirmed that the copolymers degraded into various monomers of the copolymers, which were non-toxic and biocompatible. A two-stage hydrolysis pathway was thus proposed to explain the degradation behavior of the copolymers. In vivo degradation studies performed in mice demonstrated a good in vitro and in vivo correlation for the degradation rates. In vivo clearance of the polymer was faster and without any lag phase. These copolymers are potentially advantageous for drug delivery and other biomedical applications where rapid clearance of the polymer carrier and repeated dosing capability are essential to the success of the treatment.
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