【作者】 黄丽；

【导师】 姚日生；

【作者基本信息】 合肥工业大学 ， 制药工程（专业学位）， 2021， 硕士

【摘要】 聚甲丙烯酸铵酯Ⅰ是一种良好的缓控释药用辅料,应用广泛。但目前使用的合成方法均存在单体残留量的问题。单体残留量是衡量聚甲丙烯酸铵酯Ⅰ药用辅料质量的关键指标,《药典》严格限制药用辅料中残留单体的含量。迄今为止,常用于脱除高分子中残留单体的方法主要有物理法、化学法和生物法。这类方法虽然能有效脱除残留单体,却无法提高原料利用率。爆聚法虽然能在反应过程通过提高单体转化率达到降低单体残留量的目的,却因反应剧烈存在冲料的风险。本文在爆聚法研究的基础上,在溶液聚合中通过升温引发爆聚反应解决聚甲丙烯酸铵酯Ⅰ残留单体的问题,同时完成爆聚动力学研究、爆聚工艺的研究以及爆聚树脂的结构、溶出性能研究。一、基于影响爆聚动力学的影响因素,本文重点研究升温速率、爆聚点单体浓度及升温过程中引发剂滴加量对聚合反应的影响。通过转化率-时间曲线的斜率,研究升温爆聚过程中聚合速率的变化。将转化率-时间的关系曲线转换为-ln(1-x)～1-exp(-k_dt/2)的关系曲线,通过曲线斜率研究升温爆聚过程中速率常数K的变化。研究结果表明,升高温度、提高爆聚点单体浓度及升温过程中引发剂滴加量较低,均能有效降低单体残留量。升温引发爆聚的过程中,聚合速率提高、K提高、转化率提高。但转化率提高,溶液粘度增加,影响单体扩散,单体残留量增加。故应控制爆聚点升温速率、聚点单体及引发剂浓度。二、根据单因素实验结果,以单体总残留率为响应值作响应面和等高线,以升温爆聚过程中的关键参数如升温速率、爆聚点单体浓度及升温过程中引发剂的滴加量3个因素为自变量,通过响应面实验设计对工艺进行优化。获得的最佳工艺参数:升温速率1℃/min;引发剂浓度101.25 mg;c(MMA):c(EA)=2.34:1,单体残留量低至0.39%。与目前的生产工艺对比,无须后处理工艺,同时反应时间缩短了3h。单体残留量从6.5%降至0.39%。三、以质量相当的RL100作为对照品。通过核磁、红外、热重、分子量检测及溶出分析,对树脂的结构及性能进行分析。研究结果表明,升温爆聚法制备的树脂结构以及热稳定性均与RL100一致,由于溶剂的使用反应过程中发生链转移反应,分子量偏大分布较宽。以阿司匹林为模型药物进行树脂包衣溶出研究,结果表明爆聚树脂与RL100的溶出特性差异较小。通过对溶出曲线进行动力学模拟,研究发现RL100及爆聚树脂包衣的片剂的溶出均符合一级动力学模型。更多还原

【Abstract】 Polyammonium methacrylate Ⅰ is a kind of sustained and controlled release pharmaceutical excipients,which is widely used.However,the problem of monomer residues exists in all the synthesis methods used at present.The residual amount of monomers is a key index to measure the quality of polyammonium methacrylateⅠmedical excipients..The Pharmacopoeia strictly limits the content of residual monomers in pharmaceutical excipients.So far,physical,chemical and biological methods have been used to remove residual monomers from macromolecules.Although these methods can effectively remove residual monomers,they can not improve the utilization rate of raw materials.Although the explosive polymerization method can reduce the residual amount of monomer by improving the conversion rate of monomer in the reaction process,it has the risk of flushing due to the violent reaction.Based on the study of explosive polymerization,the problem of residual monomer inPolyammonium methacrylate Ⅰ was solved by heating up to trigger the explosive polymerization.The study of explosive polymerization kinetics,explosive polymerization process,structure and dissolution properties of explosive polymerization resin were completed.1.Based on the influencing factors of detonation polymerization kinetics,this paperfocuses on the effects of heating rate,monomer concentration at detonation point and dropping amount of initiator on polymerization.Through the slope of conversion rate-time curve,the change of polymerization rate in the process of temperature-rising detonation polymerization was studied.The relation curve of conversion rate and time was transformed into the relation curve of-ln(1-x)～1-exp(-k_dt/2),and the change of rate constant K in the process of temperature-rising detonation polymerization was studied by the slope of the curve.The results showed that the residual amount of monomer can be effectively reduced by increasing the temperature,increasing the monomer concentration at the detonation point and decreasing the amount of initiator drop during the heating process.In the process of explosive polymerization,the polymerization rate,K and conversion increase.However,with the increase of conversion,the viscosity of solution increases,which affects the diffusion of monomer and increases the residual amount of monomer.Therefore,it is necessary to control the heating rate of detonation polymerization point,the concentration of polymerization monomer and initiator.2.According to the single factor experimental results,the total residual rate of monomer was taken as the response surface and contour line,and the key parameters in the process of heating detonation polymerization,such as the heating rate,the concentration of monomer at detonation polymerization point and the amount of initiator in the process of heating,were taken as independent variables.The process was optimized by response surface experimental design.The optimum process parameters were obtained as follows:heating rate 1℃/min;initiator concentration 101.25mg;C(MMA):C(EA)=2.34:1,the residual monomer as low as 0.39%.Compared with the current production process,no post-treatment process is needed and the reaction time is shortened by 3 h.The residual amount of monomer decreased from 6.5%to 0.39%.3.RL100 was used as the reference material.The structure and properties of the resin were analyzed by hydrogen nuclear magnetic spectrum,infrared spectrum,thermal stability analysis,molecular weight analysis and dissolution analysis.The results show that the structure and thermal stability of the resin prepared by temperature explosion polymerization are not different from RL100.Due to the chain transfer reaction in the reaction process,the molecular weight distribution is larger than that of RL100.Aspirin was used as the model drug to study the dissolution of resin coating.The results showed that there was little difference in the dissolution characteristics between explosion polymerization resin and RL100.The results showed that the dissolution curves of RL100 and resin coated tablets in simulated gastric juice and simulated intestinal juice conformed to the first-order kinetic model.更多还原