Gamma irradiation effects on poly(DL-lactictide-co-glycolide) microspheres.
Gamma radiation treatment plays an increasingly important role in the sterilization/sanitization of pharmaceutical products. However, irradiation may affect the stability of the product and thus its safety of use. We investigated the influence of ionizing radiation on modified release microparticulate drug delivery systems made of two types of polylactide-co-glycolide copolymers (PLG): RG 503 and RG 503H; these polymers have identical molecular weights but different chemical structures. The effect of gamma radiation on polymer stability of the raw polymers (P) and related microspheres (Ms) was evaluated. Samples were irradiated at different irradiation doses (5, 15 and 25 kGy) using 60Co as radiation source. The microspheres were prepared using the spray drying technique. Degradation of PLG and related microspheres was evaluated during six months in terms of average molecular weight (Mw) loss by gel permeation chromatography (GPC) and variation in glass transition temperature (Tg) using differential calorimetry (DSC). The presence of free radicals in the product was tested by electron paramagnetic resonance (EPR). Both P and Ms showed a trend in decreasing their Mw at time 0 as a function of irradiation dose. For RG503 the decay in Mw is always negligible for doses below 15 kGy while it is about 10% for 25 kGy. After 150 days Mw decay was 25% in the microspheres and 20% in the raw polymer. It was not possible to evaluate the radiation effect, at different storage times, for RG503H because this polymer resulted to be unstable even in the regular storage conditions without being irradiated. The concentration of radiation-induced free radicals was higher in RG 503H (both P and Ms) and they were more stable than the free radicals species observed in the case of polymer RG 503. Alterations and/or production of new radicals were observed on exposure of RG 503H microspheres to the light. Radiolytic degradation of RG 503 under vacuum is characterized by a prevalence of the chain scission events leading to a decrease of Mw. Some crosslinking can occur mainly in the post irradiation stage through the decay and coupling of the hydrogen abstraction radicals. A hydroperoxydative cycle, whose mechanism is suggested, is generated in the presence of oxygen.
Montanari
L
L
Istituto di Chimica Farmaceutica, Università degli Studi di Milano, V. le Abruzzi 53, 20131 Milano, Italia. montana@imiucca.csi.unimi.it
Costantini
M
M
Signoretti
E C
EC
Valvo
L
L
Santucci
M
M
Bartolomei
M
M
Fattibene
P
P
Onori
S
S
Faucitano
A
A
Conti
B
B
Genta
I
I
D001672:Biocompatible Materials / Q000737:chemistry* / Q000528:radiation effects*; D002152:Calorimetry, Differential Scanning; D004355:Drug Stability; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals / Q000737:chemistry; D005720:Gamma Rays; D019344:Lactic Acid / Q000737:chemistry* / Q000528:radiation effects*; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D008970:Molecular Weight; D010100:Oxygen / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry* / Q000528:radiation effects*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry* / Q000528:radiation effects*; D013242:Sterilization
D001672:Biocompatible Materials; D005609:Free Radicals; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D010100:Oxygen