RESUMEN
The aim of this study is to evaluate the specificities of the irradiation of drugs in frozen aqueous solution. The structures of the degradation products were determined to gain insight into the radiolysis mechanisms occurring in frozen aqueous solutions. Metoclopramide hydrochloride and metoprolol tartrate were chosen as models. The frozen solutions were irradiated at dry ice temperature by high energy electrons at various doses. The drug purity (chemical potency) and the radiolysis products were quantified by HPLC-DAD. Characterization of the degradation products was performed by LC-APCI-MS-MS. The structures of the radiolysis products detected in irradiated frozen aqueous solutions were compared to those detected in solid-state and aqueous solutions (previous studies). For both metoclopramide and metoprolol, solute loss upon irradiation of frozen aqueous solutions was negligible. Five radiolysis products present in traces were identified in irradiated metoclopramide frozen solutions. Three of them were previously identified in solid-state irradiated metoclopramide crystals. The two others were formed following reactions with the hydroxyl radical (indirect effect). Only one fragmentation product was observed in irradiated metoprolol frozen solutions. For both drugs, radiosterilization of frozen solutions, even at high doses (25 kGy), was found to be possible.
Asunto(s)
Preparaciones Farmacéuticas/efectos de la radiación , Soluciones Farmacéuticas/química , Esterilización/instrumentación , Agua/química , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida , Estabilidad de Medicamentos , Electrones , Congelación , Espectrometría de Masas , Metoprolol/análisis , Metoprolol/química , Modelos Químicos , Preparaciones Farmacéuticas/análisis , Radiación , Esterilización/métodos , Tecnología Farmacéutica/métodos , TemperaturaRESUMEN
The aim of this study was to assess the feasibility of radiosterilization of drugs aqueous solutions and to evaluate the effects of some additives, such as mannitol, nicotinamide and pyridoxine, which might protect the drug from degradation. Metoclopramide was selected as a model drug. The structures of the degradation products were determined to gain insight on the radiolysis mechanisms in aqueous solution in order to design strategies to lower the drug degradation. Metoclopramide hydrochloride aqueous solutions with and without excipients were irradiated either with gamma rays or high-energy electrons. HPLC-DAD was used to measure the loss of chemical potency and to quantify the degradation products which were also characterized by LC-APCI-MS-MS. Metoclopramide recovery for gamma and electron beam-irradiated solutions containing either mannitol, pyridoxine or nicotinamide meets the pharmacopoeial specifications for metoclopramide content up to a 15 kGy irradiation so that metoclopramide solutions containing these excipients might be radiosterilized at 15 kGy either with gamma rays or high-energy electrons. Structures are proposed for the majority of radiolysis products. Similar radiolysis products were detected for gamma and electron beam irradiations but the chromatographic profiles were different (differences in the distribution of radiolysis products).
Asunto(s)
Excipientes/química , Excipientes/efectos de la radiación , Preparaciones Farmacéuticas/química , Preparaciones Farmacéuticas/efectos de la radiación , Protectores contra Radiación/química , Protectores contra Radiación/efectos de la radiación , Esterilización/métodos , Cromatografía Líquida de Alta Presión , Cromatografía Liquida , Color , Electrones , Rayos gamma , Manitol/química , Manitol/efectos de la radiación , Espectrometría de Masas , Niacinamida/química , Niacinamida/efectos de la radiación , Preparaciones Farmacéuticas/administración & dosificación , Soluciones Farmacéuticas , Piridoxina/química , Piridoxina/efectos de la radiación , Radiometría , AguaRESUMEN
The degradation of irradiated human insulin in aqueous solutions was investigated in order to protect the protein against ionizing radiation. The influence of the drug concentration, excipients and irradiation temperature were studied. Aqueous solutions at pH 2 were irradiated by gamma rays or by accelerated electrons. Two different high-performance liquid chromatography (HPLC) methods were used: reverse-phase high-performance liquid chromatography (RP-HPLC)/UV and size exclusion liquid chromatography (SEC/UV) to investigate both the fragmentation and the formation of higher molecular weight proteins. In solution without excipients irradiated at ambient temperature at 10 kGy, the loss of human insulin is almost complete. Addition of radio-protecting excipients (free radicals scavengers) and cryo-irradiation allowed to decrease insulin degradation. The best radio-protector used was ascorbic acid in aqueous solution and oxidized glutathione in the frozen solutions. Only the combination of these two approaches (addition of scavenger and freezing) enables the irradiated human insulin in aqueous solution to meet the European Pharmacopoeia requirements for chemical potency (>or=90%).
Asunto(s)
Rayos gamma , Insulina/efectos de la radiación , Esterilización/métodos , Cromatografía Líquida de Alta Presión , Estabilidad de Medicamentos , Electrones , Excipientes , Congelación , Humanos , Concentración de Iones de Hidrógeno , SolucionesRESUMEN
PURPOSE: To study the chemical modifications induced upon irradiation of solid human insulin at radiosterilization doses and investigate the influence of the absorbed dose on radiolysis. MATERIALS AND METHODS: Volatile radiolytic products were monitored by gas chromatography coupled with mass spectrometry (GC-MS) and non-volatile products by two different high performance liquid chromatography (HPLC) methods: the formation of higher molecular weight proteins was assessed by size exclusion liquid chromatography whereas assays for related compounds and chemical potency tests were carried out using reverse-phase HPLC-UV. Conformational changes were investigated by measurements of circular dichroism. RESULTS: After gamma irradiation at 10 kGy, the recovery of insulin was 96.8%; higher molecular weight proteins accounted for 0.35% (relative peak area) and other related compounds (including A21 desamido insulin) represented 1.29%. No major structural changes and no volatile radiolytic compounds were detected. CONCLUSION: Human insulin samples irradiated in the solid-state at 10 kGy (gamma rays) and 14 kGy (electron-beam) meet the European Pharmacopoeia requirements and can be considered as quite stable towards radiation from a chemical analysis viewpoint.
Asunto(s)
Hipoglucemiantes/análisis , Hipoglucemiantes/efectos de la radiación , Insulina/análisis , Insulina/efectos de la radiación , Cromatografía Líquida de Alta Presión , Dicroismo Circular , Rayos gamma , Cromatografía de Gases y Espectrometría de Masas , Conformación Molecular , Peso Molecular , Espectroscopía Infrarroja Corta , VolatilizaciónRESUMEN
PURPOSE: Study the radiolysis of solid-state metoclopramide hydrochloride at various absorbed doses. Elucidate the structure of the degradation products to gain information on the radiolysis mechanisms. METHODS: Solid-state metoclopramide samples were irradiated at several doses with gamma rays and high-energy electrons to evaluate the influence of the dose rate. High-performance liquid chromatography with a diode array detector was used to measure the chemical potency as a function of the absorbed dose and to quantify the degradation products. The characterization of degradation products was performed by liquid chromatography/atmospheric pressure chemical ionization/tandem mass spectrometry. RESULTS: The degradation of solid-state metoclopramide after irradiation was negligible. No qualitative or quantitative differences were observed between gamma and electron beam irradiations (no dose rate effect). Four degradation products that were similar to metoclopramide were detected in trace levels (below 0.1% of the drug concentration) and were not unique to irradiation because they were found in lower amounts in unirradiated metoclopramide. The major degradation product formed after radiation was due to the loss of the chlorine atom from the metoclopramide molecule. CONCLUSION: Solid-state metoclopramide is radioresistant from a chemical point of view and therefore could be a suitable candidate for radiosterilization studies by either gamma rays or high-energy electrons.