论文总字数：25733字

摘 要

药物共晶是目前全世界晶体工程学前沿研究的核心问题之一。活性药物成分（API）在不改变药物本身结构的前提下通过氢键而形成药物共晶来改善其理化性质^[1]，作为可设计的药物固体形态，药物共晶因具备种类多、适用范围广的特点而广受瞩目；API通过形成药物共晶而获得知识产权保护，延长原有药物的市场周期^[2]。

茶碱类药物是用于治疗慢性阻塞性肺疾病及哮喘的常用药物^[3]。如今已经有30多种临床已知的茶碱类药物及其衍生物，最为常用的茶碱类药物包括氨茶碱、二羟丙茶碱、胆茶碱、茶碱乙醇胺等^[3][5]。

对乙酰氨基酚是一种常见苯胺类解热镇痛药，在临床上被广泛应用。其解热镇痛效果类似于非那西丁；相较阿司匹林，其效果持久而刺激性小，很少有过敏反应^[4]。

同一药物的不同固体形态通常具有不同的理化性质（其体现为不同的药效）以及制剂制备工艺。常见的药物固体形态（例如盐或溶剂化物）因为品种少或适用的药物少，在临床使用上具有一定的局限性。因此种类丰富且适用范围广的共晶已在近年来成为尤为重要的可设计药物固体形态^[1]。

关键词：茶碱 对乙酰氨基酚 药物共晶 药物固体形态

The temperature effect on the preparation of theophylline- acetaminophen co-crystal

Abstract

Drug co-crystal is currently the frontier and focus of international crystallography engineering. On the premise of not changing the drug structure, Active Pharmaceutical Ingredients (APIs) enhance the physical and chemical properties of drugs by forming drug co-crystal through hydrogen bonds. As a designable drug solid form, drug co-crystal has received a lot of attention on account of its variety of types and universal applicability. By forming drug co-crystals, APIs get intellectual property rights protection, thus extend the market cycle of original drugs.

Theophylline drugs are mainly applied to the treatment of chronic obstructive pulmonary disease and asthma. Currently, there are more than 30 kinds of clinically known theophylline drugs and the derivatives of them. The mostly commonly used theophylline drugs include: aminophylline, choline theophylline, theophylline ethanolamine, diprophylline, and so forth.

Acetaminophen is an extensively used clinical aniline antipyretic analgesics. Its effect is like that of phenacetin; compared to aspirin, its effect lasts longer and is less irritant, rarely causes allergies.

Different solid forms of same drug tend to possess different physical and chemical properties(presented as different efficacies) and different preparation techniques. Common solid forms, such as solvent compounds and salts, are to some extent limited in clinical use due to the uniformity of its types and its lack in applicable drugs. Therefore, co-crystals, which have variable types and are universally applicable, have been increasingly significant as a designable drug solid form in recent years.

Keywords: Theophylline Acetaminophen Drug co-crystal Drug solid form

目录

摘要 1

Abstract 1

第一章 绪论 3

1.1课题研究背景 3

1.2 药物共晶 3

1.2.1 药物共晶的定义 4

1.2.2 共晶形成原理 5

1.2.3 药品分析 6

1.2.4 药物共晶表征方法 10

1.2.5 药物共晶热力学稳定性 13

第二章 实验内容与方案 17

2.1 实验仪器与药品 17

2.2 实验方案 17

2.2.1共晶溶液浓度线性关系式 17

2.2.2 实验流程设计 18

2.3 实验内容 19

2.3.1高效液相色谱检测条件的确定 19

2.3.2 标准曲线的绘制 21

2.3.3温度对THEO、APAP、THEO-APAP混合溶液及共晶制备液中对APAP、THEO的浓度关系的影响 22

第三章 实验结果与分析 24

3.1 实验 24

3.1.1 温度对共晶溶解度的影响 24

3.1.2温度对THEO-APAP共晶形成点的影响 27

第四章 结论与展望 32

4.1 结论 32

4.2 展望 33

参考文献 34

致谢 38

第一章 绪论

1.1课题研究背景

结晶即为物质从液态（熔融状态、溶液状态）或气态中析出形成晶体的过程。由于结晶过程具有高效、低污染、耗能少，产品的纯度高等众多优点，结晶被广泛应用于化工、医药、材料等多个行业。

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