传统的宫内节育器（Intrauterine Device, IUD）主要是通过支架结构释放活性物 质铜离子来达到避孕效果，并通过在 IUD 上负载药物吲哚美辛（Indomethacin，IDM）， 释放活性物质 IDM 来消炎止血，减轻 IUD 的副反应。 本文采用结晶法以 IDM 和一水醋酸铜，以乙醇作为溶剂合成了配合物吲哚美辛 铜（Cu 2 (Indo) 4 (OH 2 ) 2 1.5H 2 O ，copper-indomethacin，简称 Cu-IDM），并对其合成 工艺和后处理工艺及理化性质进行了研究表征，研究其作为 IUD 活性物质，能同时 释放铜离子和 IDM 的可能性。 在 Cu-IDM 的合成工艺研究上，研究了原料配比、反应温度和反应时间对产率 的影响来优化其合成工艺。从实验结果可以看出，Cu-IDM 的产率随原料配比、反应 温度、反应时间的改变呈现一定的规律，当原料配比为 2:1.1，反应温度为 50℃，反 应时间控制在 30h 左右时产率达到最优；通过研究后处理工艺对产物纯度的影响来 优化后处理方法，实验结果表明，后处理时洗涤剂水和乙醇的用量、次数和洗涤顺 序对产物的纯度和稳定性会产生影响，先用水洗涤两次，再用乙醇洗涤四次，可以 基本除去剩余的原料，使得产物的纯度达到 95%；增加水洗次数或者先用乙醇后用 水洗涤，会使 Cu-IDM 不稳定发生分解，从而降低的 Cu-IDM 最终纯度。 通过 1 H-NMR、XRD、SEM 、DSC 、TG 等表征手段对 Cu-IDM 的组织结构及 理化性质进行了表征。由 1 H-NMR 结果表明，由 IDM 成功的合成了 Cu-IDM，并且 通过 XRD 表明，Cu-IDM 为三斜晶型；SEM 结果表明 Cu-IDM 为三棱体结构，粒径 约为 1μm；DSC 结果表明其熔点范围为 160.7-177.5℃，吸热范围较宽；TG 的结果 表明 165℃以前 Cu-IDM 只发生脱水反应，而 Cu 与 IDM 之间的配位键不变。 通过称重法研究了 Cu-IDM 在模拟宫腔液（SUS）和水中的溶解度，并结合紫外 可见吸收法研究 Cu-IDM 在 SUS 中的分解性能，验证了 Cu-IDM 在 IUD 上的应用的 可行性；同时通过紫外可见吸收法研究 Cu-IDM 在两种有机溶剂乙酸乙酯和乙腈中 的溶解性能，结果表明 Cu-IDM 在乙酸乙酯中的溶解性大，综合考虑有机物的毒性 大小，以直接浸渍法将其负载在 IUD 上时以乙酸乙酯作为溶剂最好。 关键词：吲哚美辛 吲哚美辛铜 合成工艺 后处理工艺 理化性质华 中 科 技 大 学 硕 士 学 位 论 文 II Abstract The traditional Intrauterine Device（IUD）mainly through the trestle structure and release the active material of copper ions to achieve contraceptive effect, and through loading the drug of Indomethacin (IDM) in IUD to reduce the side effects of IUD by releasing the active material of IDM to diminish inflammation bleeding, In this article, the crystallization method was used to synthesis the complexes copper-indomethacin(Cu-IDM) with IDM and water copper acetate in ethanol as the solvent. And the synthesis process and the post-processing technology was researched and the physicochemical property of Cu-IDM was characterized, which was used to prove the Cu-IDM can be used in IUD as the active substance to release copper ions and IDM. In the synthetic technology of Cu-IDM research, we got the optimal synthetic process by researching the influence of the raw material ratio, the reaction temperature and the reaction time in the production rate. And the experimental results show that the yield of the Cu-IDM can achieve optimal with the ratio of raw materials for 2:1.1, the reaction temperature for 50℃ and the reaction time controling in about 30h. Through research on the post-processing to optimize the product purity technology, and the experimental results show that in the post-processing the amount of water and ethanol, the washing time and the order of washing influence the purity and stability of Cu-IDM. The feedstock remaining after reaction can be removed by washing twice with water, and then washing four times with ethanol to get the product with high purity. The Cu-IDM will unstable while increaseing the amount of water or using ethanol first, which will reduce the purity of the product. The organization structure and the physicochemical property of Cu-IDM was characterized by 1 H-Nuclear magnetic resonance, X-ray diffraction, scanning electron microscopy, differential scanning calorimetry and thermogravimetric analysis. By 1 H-NMR results show that we successfully synthesized Cu-IDM by IDM. And through the XRD we know that Cu-IDM for tricinic crystal. SEM results show that Cu-IDM for 3 arris body structure, and the size is about 1 μ m. The DSC results show that the melting point range from160.7 to177.5℃. The TG results show that before 165℃ Cu-IDM has dehydration reaction, and the coordinate bonds between Cu and IDM are unchanged.华 中 科 技 大 学 硕 士 学 位 论 文 III The gravimetric analysis was used to get the the solubility of Cu-IDM in simulation of uterine liquid (SUS) and water. Use the result and combined with uv-visible method to study decomposition performance of Cu-IDM in SUS, which verifies the application feasibility of Cu-IDM in IUD. Uv-visible method was used to study the solubility of Cu-IDM in two organic solvent acetic ester and acetonitrile. The results show that Cu-IDM is more soluble in ethyl acetate than acetonitrile. Considering the toxic of organic matter, acetic ester can be the solvent when use straight dipping process to load Cu-IDM in IUD. Key words: indomethacin, copper-indomethacin, synthetic process, post-processing physicochemical property华 中 科 技 大 学 硕 士 学 位 论 文 IV 目 录 摘要...............................................................................................................I Abstract...........................................................................................................II 1 绪论 1.1 IUD 概述 ..............................................................................................(1) 1.2 活性 IUD 的作用机制 .........................................................................(3) 1.3 活性 IUD 的常见副反应与预防措施 .................................................(4) 1.4 Cu-IDM 作为潜在活性物质的优势....................................................(7) 1.5 本文的研究目的及意义 ....................................................................(10) 2 实验过程 2.1 实验材料.............................................................................................(12) 2.2 实验设备.............................................................................................(13) 2.3 Cu-IDM 的制备..................................................................................(13) 2.4 Cu-IDM 的结构与理化性质表征......................................................(15) 3 Cu-IDM 的合成工艺 3.1 原材料配比对 Cu-IDM 产率的影响.................................................(20) 3.2 合成温度对 Cu-IDM 产物及产率的影响 ........................................(21) 3.3 反应时间对产率的影响 ....................................................................(23) 3.4 提纯工艺对 Cu-IDM 纯度的影响.....................................................(24) 3.5 本章小结.............................................................................................(26) 4 Cu-IDM 的结构与理化性质华 中 科 技 大 学 硕 士 学 位 论 文 V 4.1 Cu-IDM 的结构表征..........................................................................(28) 4.2 Cu-IDM 的熔点及热力学行为..........................................................(33) 4.3 Cu-IDM 在水和 SUS 中的溶解度与分解性能 ................................(36) 4.4 Cu-IDM 在两种有机溶剂中的溶解性..............................................(38) 4.5 本章小结.............................................................................................(43) 5 全文总结 5.1 主要结论.............................................................................................(44) 5.2 工作展望.............................................................................................(45) 致 谢..........................................................................................................(46)