头孢呋辛钠反应及结晶过程研究-化学工程专业论文.docx

摘要
头孢呋辛钠是头孢菌素类抗生素,为国家基本药物,在临床上被广泛应用。目前国内头孢呋辛钠产品普遍存在色级高、纯度低、聚结严重、晶习不理想、稳定性差等问题,本文针对头孢呋辛钠现存的问题,对结晶过程进行了系统深入的研究,并开发了一种新结晶工艺。
首先进行了头孢呋辛热力学研究。采用动态法分别测定了头孢呋辛酸在混合溶剂体系(水+乙醇、溶剂 A+丙酮、水+溶剂 A)中、头孢呋辛钠α晶型在混合溶剂体系(水+溶剂 A、水+溶剂 A+乙醇、水+溶剂 A+正丙醇、水+溶剂 A+溶剂 B)中和头孢呋辛钠β晶型在纯溶剂(水、溶剂 A)中的溶解度数据,并用 Apelblat 简化经验方程、(CNIBS)/Redlich-Kister 方程、Jouyban-Acree 方程和 van’t Hoff 方程对实验数据进行了拟合,计算了相关热力学性质,为工艺设计和优化提供了基础数据。
然后研究了头孢呋辛钠在溶剂中的降解动力学。采用高效液相色谱(HPLC) 分析手段,测定了头孢呋辛钠降解动力学数据,确定了头孢呋辛钠在水/溶剂 A
(,V/V)混合溶剂中和在纯水中的降解反应级数,对比了在两种溶剂体系中的降解速率,系统地研究了初始浓度、温度、pH 值等因素对头孢呋辛钠在水+ 溶剂 A 溶剂体系中降解的影响,为工艺优化提供了理论依据。
最后对头孢呋辛钠反应及结晶工艺进行了设计和优化,包括溶剂体系的选择, 结晶方式的确定,温度、成盐剂、pH 值、搅拌速率、溶析剂等工艺参数的优化, 最终确定了新工艺最佳操作条件。该工艺下得到的头孢呋辛钠产品具有色级低、收率高、结晶度高、形态好、稳定性好的优点。
以上研究未见有文献报道。
关键词:头孢呋辛钠;溶解度;降解动力学;耦合结晶;工艺优化
ABSTRACT
Cefuroxime sodium, the national essential drug, is a kind of cephalosporins. This drug is widely used in chemical and pharmaceutical industry. To present, the domestic cefuroxime sodium monly have the problems of high color grade, low purity, serious coalescence, poor crystal habit and poor stability. In this paper, aiming at solving these existing problems, the crystallization process of cefuroxime sodium was studied systematically and deeply. A new crystallization method of cefuroxime sodium was developed.
Firstly, the thermodynamic properties of cefuroxime were studied. The dynamic method was used to measure the solubility of cefuroxime acid in mixed solvent systems (water + ethanol, solvent A + acetone, water + solvent A), the solubility of cefuroxime sodium (form α) in mixed solvent systems (water + solvent A, water + solvent A + ethanol, water + solvent A + 1-propanol, water + solvent A + solvent B) and the solubility of cefuroxime sodium (form β) in pure solvents (water, solvent A). What’s more, the simplified Apelblat equation, the (CNIBS)/Redlich-Kister equation, the Jouyban-Acree equation and the van’t Hoff equation were used to fit the experimental data. The relevant thermodynamic properties were also calculated in