鄰位與間位硝基取代之硝基苯基-1,4-二氫?啶類鈣離子阻斷劑在醇類溶媒中之光安定性比較研究

1,4-Dihydropyridine calcium channel blockers are widely used for the treatment of coronary heart disease in clinical therapy. However, they are light sensitive when exposed to fluorescent lamps or sunlight. These drugs are mostly unstable or even phototoxic when stored on shelves under the exposure of household light. In order to unveil the behavior of their photochemical pathway, a systematic study of the photodegradation of 1,4-dihydropyridine was undertaken. Furthermore, the elucidation of the photostability characteristics of 1,4-dihydropyridine family is essential for the development of new dosage forms. In this study, we classify 1,4-dihydropyridine derivatives into two groups, namely 4-(2''-nitrophenyl)-1,4- dihydropyridines (represented by nifedipine, NIF) and 4-(3''- nitrophenyl)-1,4- dihydropyridines (represented by nicardipine, NIC). The objective is to make a comparison between two different classes of drugs in alcoholic solution under irradiation. The photodecomposition products were separated and identified using UV, IR, MS and NMR spectroscopies. It was found that NIF was swiftly converted into nitroso-derivative (NIF1) under the irradiation of a fluorescent lamp. NIC showed better stability under the same irradiation condition. When NIC was exposed to a high pressure mercury lamp, three new photodegradation products of NIC were observed and their structures identified. The main degraded products was a 4-(3''-nitrophenyl) pyridine analogue (NIC1), and others two: a 4-(3''aminophenyl) pyridine analogue (NIC2) and a trans-azoxy dimer (NIC3) of NIC. The influential factor with respect to molar concentration, solvent, temperature and aerobic condition associated with the photodegradation were carefully investigated. The results of concentration effect showed that both drugs are best described by the first-order kinetics at lower concentration; at higher concentrations, the kinetics are gradually experiencing a transition to the zeroth-order. According to the Arrhenius equation, the activation energy of NIF and NIC are found to be 0.68 and 4.65 kcal/mol, respectively. The kinetics of NIF in three different alcoholic solvents was found to be no significant difference. The photodegradation of NIC was slower in the presence of oxygen which implies O2 molecules acting as oxidant in competing for hydrogen atoms. The photolysis mechanism of NIF is postulated to undergo a sigmatropic rearrangement via a disproportionation reaction, while NIC apparently undergoes a series of the photo- reduction pathways under irradiation leading to a complex formation of reduced products.

關鍵字

"1 ； 4-二氫□啶類鈣離子阻斷劑；光化學反應；光安定性；濃度；溶媒；溫度；氧氣；光分解反應；尼菲迪平；尼卡迪平；動力學；尼菲迪平；尼卡迪平" ；藥物學

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並列關鍵字

"1 ； 4-dihydropyridine calcium channel blockers ； Photochemical ； Photostability ； Concentration ； Solvent ； Temperature ； Aerobic ； Photodegradation ； Nifedipine ； nicardipine ； kinetics ； photodegradtion" ； PHARMACOLOGY

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鄰位與間位硝基取代之硝基苯基-1,4-二氫?啶類鈣離子阻斷劑在醇類溶媒中之光安定性比較研究

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