衣康酸酯改性丙烯酸树脂的合成及其医药应用
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摘要
本文概述了药用聚丙烯酸酯乳液的特点、制备方法、应用情况及发展前景,并探讨了其聚合机理。在此基础上,作者主要进行了以下研究工作。
(1)系统讨论了乳化剂用量、单体滴加时间、搅拌器转速及预乳化温度等因素对制备混合单体预乳化液稳定性的影响,通过单因素实验确定较佳制备条件为:乳化剂M-2用量2.5%、单体滴加时间30min、预乳化温度40℃、搅拌器转速500rmp。
(2)以衣康酸二正丁酯(DBI)、丙烯酸乙酯(EA)、甲基丙烯酸甲酯(MMA)和丙烯酸(AA)为单体,选择可反应型乳化剂M-1、M-2为复合乳化体系,过硫酸钾(KPS)为引发剂,通过预乳化半连续种子乳液聚合方法,合成了固含量为33.82%的EA/MMA/AA/DBI药物包衣用四元共聚物乳液。探讨了反应条件对单体转化率和平均粒径的影响,考察了乳液体系的凝胶率、稳定性以及共聚物膜的吸水率。借助于粒度分布仪、红外光谱仪(IR)、差示扫描热分析仪(DSC)、凝胶色谱仪(GPC)和透射电镜(TEM)表征了EA/MMA/AA/DBI共聚物乳液的特性:玻璃化转变温度Tg为6.27℃,共聚物的相对分子质量M w=7.8428×105,M n=3.3373×105,分散性Vp= M w/ M n=2.35,乳胶粒呈球形,平均粒径为100nm。通过四因素三水平正交试验,得出了EA/MMA/AA/DBI共聚物乳液的最佳合成条件为:乳化剂用量5.0%,引发剂用量0.5%,AA含量1.0%,DBI用量0.5%,反应温度80℃,反应时间4h。此时,粒径分布较窄,乳液性能优良。实验结果表明,加入极少量的衣康酸二正丁酯可使共聚物膜的吸水率明显降低。
(3)采用减压蒸馏-汽提法和微波辐射后聚合-汽提法分别脱除所制备的共聚物乳液中的残留单体。结果表明,减压蒸馏-汽提法时间长,能耗大,明显降低产品质量;微波辐射后聚合-汽提法能在短时间(6min)内即可大幅提高转化率,降低残单含量,且对产品质量无损,此法对体系中残余单体的脱除效率较高。
(4)将EA/MMA/AA/DBI共聚物乳液对盐酸二甲双胍素片进行薄膜包衣,制成缓控释制剂,研究其应用性能。通过单因素试验考察了包衣液浓度、衣膜厚度(素片增重量)、喷枪-片床距离、喷液量(蠕动泵转速)、后处理温度以及后处理时间等因素对药物释放的影响,确定了包衣过程中各变量的较佳值:包衣液浓度20%(粘度<0.5Pa·s),衣膜厚度3.00%,喷枪-片床距离25cm,喷液量0.8 rpm,后处理温度室温,后处理时间1h。
In this paper, the properties, preparation method, application and development prospects were summarized, and the polymerization mechanisms were also discussed. On the basis, some research tasks were done as follows.
(1) The effect of such factors as dosage of emulsifier, pre-emulsification tempreture,stirrer rotate speed on pre-emulsified liquid stability were discussed systematically. By single factor experiment, more optimum conditions was determined: dosage of emulsifier M-2 was 2.5%, monomer addition time was 30min, stirrer rotate speed was 500rmp, pre-emulsification tempreture was 40℃.
(2) Using dibutyl itaconate(DBI), ethyl acrylate(EA), methyl methacrylate(MMA) and acrylic acid(AA) as raw monomer materials, and reactive emulsifiers M-1, M-2 as complex emulsifier system and potassium peroxy-sulfate(KPS) as initiator system, EA/MMA/AA/DBI quadripolymer emulsion of pharmaceutical coating acrylate with solid content of 33.82 percent was prepared by pre-emulsified seeded emulsion polymerization. Effects of reaction factors on monomer conversion and mean diameter were studied systematically, and gel ratio, stability of emulsion system and water absorption ratio of copolymer film were also studied. The copolymer was tested and characterized by particle size distribution, infra-red spectrum(IR), Differential Scanning Calorimetry (DSC), Gel Permeation Chromatography (GPC) and Transmission Electron Microscope(TEM). DSC thermogram of copolymer showed that glass temperature(Tg) was 6.27℃. Results of GPC showed that weight-average molecular weight (M w) was equal to 7.8428×105, number-average molecular weight (M n) was 3.3373×105, and poly dispersion was 2.35. Particle morphology of the coating system was examined by TEM. Spherical particles were observed and the mean particle size was about equal to 100 nm. By orthogonal test method, the most optimum reaction conditions were as follows: emulsifier dosage was 5.0%, initiator dosage was 0.5%, AA content was 1.0%, DBI content was 0.5%. The synthetic latex had narrow size distribution and excellent properties. Results showed that water absorption ratio was reduced evidently after adding little DBI.
(3) Methods of vacuum distillation-stripping and microwave irradiation post-polymersion-stripping were used separatedly to remove the residual monomer of the copolymer emulsion. Results showed that time needed was too long, energy cost was greatly and procuct quality was reduced through vacuum distillation-stripping; monomer conversion was increased and residual monomer was decreased sharply in only 6 minutes, product was little damaged by microwave irradiation post-polymersion-stripping, and its efficiency was very high.
(4) Using EA/MMA/AA/DBI copolymer emulsion prepared to coat metformin hydrochloride into sustained-controlled release preparation, application property of the system was researched. Effect of coating solution concentration, thickness of coating film(weight increased of the troche), distance between spray gun and troche bed, dosage of coating solution sprayed (squirm pump rotate speed) on the drug release were studied by single factor experiment. The optimum variables in the coating process were as follows: coating solution concentration was 20% (viscidity<0.5Pa·s), thickness of coating film(weight increased of the troche) was 3.0%,distance between spray gun and troche bed was 25cm,dosage of coating solution sprayed (squirm pump rotate speed) was 0.8 rpm,post-disposal temperature was room temperature and post-disposal time was 1h.
(1)系统讨论了乳化剂用量、单体滴加时间、搅拌器转速及预乳化温度等因素对制备混合单体预乳化液稳定性的影响,通过单因素实验确定较佳制备条件为:乳化剂M-2用量2.5%、单体滴加时间30min、预乳化温度40℃、搅拌器转速500rmp。
(2)以衣康酸二正丁酯(DBI)、丙烯酸乙酯(EA)、甲基丙烯酸甲酯(MMA)和丙烯酸(AA)为单体,选择可反应型乳化剂M-1、M-2为复合乳化体系,过硫酸钾(KPS)为引发剂,通过预乳化半连续种子乳液聚合方法,合成了固含量为33.82%的EA/MMA/AA/DBI药物包衣用四元共聚物乳液。探讨了反应条件对单体转化率和平均粒径的影响,考察了乳液体系的凝胶率、稳定性以及共聚物膜的吸水率。借助于粒度分布仪、红外光谱仪(IR)、差示扫描热分析仪(DSC)、凝胶色谱仪(GPC)和透射电镜(TEM)表征了EA/MMA/AA/DBI共聚物乳液的特性:玻璃化转变温度Tg为6.27℃,共聚物的相对分子质量M w=7.8428×105,M n=3.3373×105,分散性Vp= M w/ M n=2.35,乳胶粒呈球形,平均粒径为100nm。通过四因素三水平正交试验,得出了EA/MMA/AA/DBI共聚物乳液的最佳合成条件为:乳化剂用量5.0%,引发剂用量0.5%,AA含量1.0%,DBI用量0.5%,反应温度80℃,反应时间4h。此时,粒径分布较窄,乳液性能优良。实验结果表明,加入极少量的衣康酸二正丁酯可使共聚物膜的吸水率明显降低。
(3)采用减压蒸馏-汽提法和微波辐射后聚合-汽提法分别脱除所制备的共聚物乳液中的残留单体。结果表明,减压蒸馏-汽提法时间长,能耗大,明显降低产品质量;微波辐射后聚合-汽提法能在短时间(6min)内即可大幅提高转化率,降低残单含量,且对产品质量无损,此法对体系中残余单体的脱除效率较高。
(4)将EA/MMA/AA/DBI共聚物乳液对盐酸二甲双胍素片进行薄膜包衣,制成缓控释制剂,研究其应用性能。通过单因素试验考察了包衣液浓度、衣膜厚度(素片增重量)、喷枪-片床距离、喷液量(蠕动泵转速)、后处理温度以及后处理时间等因素对药物释放的影响,确定了包衣过程中各变量的较佳值:包衣液浓度20%(粘度<0.5Pa·s),衣膜厚度3.00%,喷枪-片床距离25cm,喷液量0.8 rpm,后处理温度室温,后处理时间1h。
In this paper, the properties, preparation method, application and development prospects were summarized, and the polymerization mechanisms were also discussed. On the basis, some research tasks were done as follows.
(1) The effect of such factors as dosage of emulsifier, pre-emulsification tempreture,stirrer rotate speed on pre-emulsified liquid stability were discussed systematically. By single factor experiment, more optimum conditions was determined: dosage of emulsifier M-2 was 2.5%, monomer addition time was 30min, stirrer rotate speed was 500rmp, pre-emulsification tempreture was 40℃.
(2) Using dibutyl itaconate(DBI), ethyl acrylate(EA), methyl methacrylate(MMA) and acrylic acid(AA) as raw monomer materials, and reactive emulsifiers M-1, M-2 as complex emulsifier system and potassium peroxy-sulfate(KPS) as initiator system, EA/MMA/AA/DBI quadripolymer emulsion of pharmaceutical coating acrylate with solid content of 33.82 percent was prepared by pre-emulsified seeded emulsion polymerization. Effects of reaction factors on monomer conversion and mean diameter were studied systematically, and gel ratio, stability of emulsion system and water absorption ratio of copolymer film were also studied. The copolymer was tested and characterized by particle size distribution, infra-red spectrum(IR), Differential Scanning Calorimetry (DSC), Gel Permeation Chromatography (GPC) and Transmission Electron Microscope(TEM). DSC thermogram of copolymer showed that glass temperature(Tg) was 6.27℃. Results of GPC showed that weight-average molecular weight (M w) was equal to 7.8428×105, number-average molecular weight (M n) was 3.3373×105, and poly dispersion was 2.35. Particle morphology of the coating system was examined by TEM. Spherical particles were observed and the mean particle size was about equal to 100 nm. By orthogonal test method, the most optimum reaction conditions were as follows: emulsifier dosage was 5.0%, initiator dosage was 0.5%, AA content was 1.0%, DBI content was 0.5%. The synthetic latex had narrow size distribution and excellent properties. Results showed that water absorption ratio was reduced evidently after adding little DBI.
(3) Methods of vacuum distillation-stripping and microwave irradiation post-polymersion-stripping were used separatedly to remove the residual monomer of the copolymer emulsion. Results showed that time needed was too long, energy cost was greatly and procuct quality was reduced through vacuum distillation-stripping; monomer conversion was increased and residual monomer was decreased sharply in only 6 minutes, product was little damaged by microwave irradiation post-polymersion-stripping, and its efficiency was very high.
(4) Using EA/MMA/AA/DBI copolymer emulsion prepared to coat metformin hydrochloride into sustained-controlled release preparation, application property of the system was researched. Effect of coating solution concentration, thickness of coating film(weight increased of the troche), distance between spray gun and troche bed, dosage of coating solution sprayed (squirm pump rotate speed) on the drug release were studied by single factor experiment. The optimum variables in the coating process were as follows: coating solution concentration was 20% (viscidity<0.5Pa·s), thickness of coating film(weight increased of the troche) was 3.0%,distance between spray gun and troche bed was 25cm,dosage of coating solution sprayed (squirm pump rotate speed) was 0.8 rpm,post-disposal temperature was room temperature and post-disposal time was 1h.
引文
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