ABSTRACT:The rates of change of polymer properties (glass transition temperature, weight fraction sorbed water, and polymer molecular weight) were determined in poly (DL-lactide-co-glycolide) films under accelerated storage conditions. Films were stored at 70 C and 95%, 75%, 60%, 45%, or 28% relative humidity. Weight fraction sorbed water was determined by thermogravimetric analysis, the glass transition temperature (Tg mix ) of the polymer/water mixture by modulated temperature differential scanning calorimetry, and PLGA number-average molecular weight (M n ) by size exclusion chromatography (SEC).Rates of moisture increase and Tg mix decrease were related to the decrease in PLGA M n through a modification of the Gordon-Taylor equation. Understanding the relative rates of polymer physical and chemical degradation will allow for improved design of PLGA formulations that control rates of drug delivery and preserve drug stability.
The effect of pH modifying excipients on the chemical stability of a model peptide (VYPNGA) and the degradation of poly(DL-lactide-co-glycolide)(PLGA) was studied in PLGA films under accelerated storage conditions. pH modifiers included a basic amine (proton sponge), a basic salt (magnesium hydroxide) and two pH buffers (ammonium acetate and magnesium acetate). Changes in film pH were monitored using 13 C NMR, peptide degradation products were quantified by LC/ MS/MS and PLGA degradation was analyzed by TGA, DSC and SEC. Inclusion of pH modifiers had little impact on PLGA degradation. The proton sponge affected an initial decrease in pH but reduced peptide deamidation and chain cleavage relative to an unbuffered control. Magnesium hydroxide produced an initial increase in pH but also showed increased peptide deamidation. Ammonium acetate decreased pH and increased peptide chain cleavage, presumably due to increased PLGA hydrolysis. Magnesium acetate buffer increased the initial pH but resulted in increased peptide loss. The extent of peptide acylation increased in all formulations, most notably in the proton sponge modified films. The effectiveness of pH modifiers in PLGA formulations under storage conditions is dependant on both the mechanism of pH alteration and the peptide degradation reaction of interest.
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