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
Comparative Photostability Studies of o-Nitrophenyl and m- Nitrophenyl 1,4-Dihydropyridine Calcium Channel Blocker in Alcoholic Solvents
中文摘要
1,4-二氫啶類鈣離子阻斷劑在臨床上用於治療心血管疾病，此類藥品具有光
敏感性，當暴露於螢光燈或日光下不安定，在儲架期中若經光線照射，甚至有 光毒性之顧慮，為了解其光化學反應途徑，本研究進行一系列之光分解相關實
驗，評估1,4-二氫啶類衍生物之光安定性，以作為新劑型開發之參考。研究中
將1,4-二氫啶類衍生物分成兩組：一為4-(2''-硝基苯基)-1,4-二氫 啶，硝基在鄰位的衍生物，代表之模式藥物為尼菲迪平
；另一為4-
(3''-硝基苯基)-1,4-二氫啶，硝基在間位的衍生物，代表之模式藥 物為尼卡迪平，比較此二種不同取代之藥物在醇性媒中之光解情形，並利用 UV、IR 與 NMR 等光譜鑑定其光解產物結構。
本研究發現尼菲迪平在螢光燈照射下會快速轉變成其亞硝基衍生物(NIF1)，尼 卡迪平在相同的照射條件下則較為安定。當尼卡迪平暴露於高壓汞燈下，會進行 光解反應，經鑑定確認結構之產物有3 個，包括主產物為 4-(3''-硝 基苯基)啶衍生物(NIC1)，另 2 個產物分別是 4-(3''-胺基苯基)啶 衍生物(NIC2)與反式氧化偶氮雙聚體(NIC3)。有關濃度、溶媒、溫度及氧氣對光分 解反應影響之研究方面，濃度效應顯示二種模式藥物均於較低濃度時呈現擬一 階動力學模式，而較高濃度時，漸過渡為擬零階的現象；溫度效應方面，依阿 瑞尼士方程式可分別計算出尼菲迪平與尼卡迪平之活化能為0.68 kcal/mol 與 4.65 kcal/mol；尼菲迪平在三種醇性溶媒中進行光分解反應，發現反應速率並無 顯著差異；另在氧氣效應發現，氧的存在對尼卡迪平光分解有減緩的作用，暗 示氧分子的作用如氧化劑，會競爭氫原子。尼菲迪平的光分解機轉可能經由分子
內的不均勻反應進行sigmatropic 重排反應，而卡菲迪平則於照光後進行一系列
的光還原反應，形成複雜的還原產物。
英文摘要
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 betterstability 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.
