第一部分 : 發展非固醇類抗炎劑安定性指標能力之高壓液相層析分析法
-- 托美丁和佐美酸 第二部份 : 托美丁的光安定性研究
托美丁 (TLM) 和佐美酸 (Z) 為光敏感的非固醇類抗炎劑 (NSAID) 。首先將托美丁和佐
美酸之甲醇溶液以 Hanovia 200W 的高壓汞燈照射下分別觀察到托美丁會分解成 TLM-1
至 TLM-8 八種光解產物 ; 而佐美酸會分解成 Z-1 至 Z-4 四種產物。除了利用製備型高
壓液相層析儀來單離這些光解產物外並且以 UV 、 IR 、 MS 、 NMR 和 LC-MS 光譜法
來一一解明光解產物的化學結構。
其次，為了要發展一個快速、敏感度高及準確的安定性指標的高壓液相層析法來定量托
美丁和佐美酸的降解情況並利用其在標準溶液中、酸中、鹼中和光照情況下來作一波峰
的純度確效。對托美丁的分析方法是用 Inertsil ODS-3V 管柱，移動相則採甲醇 : 0.3%
醋酸為 64: 36 (v/v) ; 而對佐美酸的定量亦用相同管柱，移動相為乙晴 : 甲醇 : 0.3% 醋
酸為 2: 64: 34 (v/v/v) ， UV 偵測器則同樣設定為 254 nm 。發展出的分析方法的相關統
計敘述包含有高壓液相層析系統規範、波峰純度完整以及光解產物和原料藥之間的解析
度，及日內、日間差異分別在 2.3% 和 4% 以內，回收率亦在 97.14%~101.73% 之間。
我們所建立的分析方法表現出良好的選擇性和特異性，適合用來作為托美丁 (TLM) 和
佐美酸 (Z) 的光安定性的分析。
托美丁 (TLM) 和佐美酸 (Z) 在甲醇溶媒或是含水甲醇溶媒的光降解速率有顯著差距。托
美丁 (TLM) 和佐美酸 (Z) 在甲醇溶液中的光降解動力學，若以一階次作圖時的 k 值相差
將近 10 倍。而後再以光動力學反應較快之托美丁 (TLM) 以不同濃度、不同醇類溶媒、
不同含水的甲醇溶液以期盼研究出托美丁 (TLM) 的光動力學模式。本研究發現托美丁
(TLM) 在高濃度呈現零階次動力學模式，至於三種醇類溶媒中，認為托美丁 (TLM) 的
動力學和介電係數 (dielectric constant) 呈現反比的情況，可表示托美丁 (TLM) 的動力學
可能是經由自由基反應途徑，而非離子化反應途徑。
Ⅰ.Development of Stability-indicating High Performance Liquid Chrom
atographic Assay Methods of NSAID Drugs--- Tolmetin and Zomepirac
II.Photostability study of Tolmetin
Tolmetin (TLM) and Zomepirac (Z) are used as photosensitizing nonsteroidal antiinflammatory drugs (NS AIDs). When TLM and Z were irradiated by a Hanovia 200W high pressure mercury lamp in methanol, a t otal of 8 photoproducts of TLM; TLM-1 to TLM-8 and 4 photoproducts of Z; Z-1 to Z-4 photoproducts we re observed, respectively. Using preparative HPLC, photoproducts were isolated and their chemical structu res were elucidated by UV 、 IR 、 MS 、 NMR and LC-MS spectroscopies.
Next, a rapid, sensitive, and accurate stability-indicating high perfor- mance liquid chromatographic assay method for determining the degra- dation of TLM and Z was developed and vali- dated under acidic, basic, or photo-irradiated conditions. The quantitation was monitored with an Inertsil ODS-3V column using a m obile phase of methanol- 0.3%acetic acid = 64:36 (v/v) for TLM and acetonitrile- methanol - 0.3%acetic = 2:64:34(v/v) for Z detector set at 254nm. The related satistics of the developed methods including the syste m criteria, peak integrity, and resolution among the parent drug and its degradation products were calculate d. The C.V.(%) of intraday and interday tests were lower than 2.3% and 4% , respectively. The percent rec overy were between 97.14% ~ 101.73 %. Our established HPLC assay method shows good selectivity and specificity which is suitable for the stability measurement of TLM and Z.
The rates of photodegradation between TLM and Z present significant difference, no mater the solvent is
MeOH or 20% MeOH/H2O. When proceeding first order graphical analysis of these two compounds, we fi
nd that k of TLM is almost ten folds to B. After that, we use TLM, which possess more sensitive property t
o UV light. With different concentrations, alcohol solvents, and concentrations of 20% MeOH/H2O, to loo
k forward to find out the exact photokinetic model of TLM. In our experimental model, the kinetic of TLM
of high concentration is zero order. As for the results of using three alcoholic solvents, they showed an inv
erse proportional relationship between kinetics and dielectric constant of TLM. Hence we supposed that ph
otokinetics of TLM might go through free radical reaction instead of ionic reaction.
