对乙酰氨基酚分散片的制备

对乙酰氨基酚分散片的制备 药剂 对乙酰氨基酚分散片制备及其质量检查 指导教师: 姓 名: 学 号: 班 级: rAt present, we have formed a "three-three" Park. …… Industrial Park, according to ... ... The instructions of comrade, focus on development needs in the next decade, based on the original, and then extended the 6 square kilometers. Of the Park, to further improve the roads, power supply, communications, water supply and drainage and sewage pipe network and other infrastructure, to achieve full coverage of infrastructure and interconnection with the facilities and raise capacity. Each park to determine 1 leading industries, in particular stone Materials, cans, gloves, through guided, force and other measures to promote the "road company" Park, industrial agglomeration. Currently, to focus on building better ... ... Industrial Park, ... ... Wood Park as the starting area of the industrial park, planners need to take out plan, start construction as soon as possible, undertake in a timely manner ... ... Transfer of the wood industry. This opportunity slip by, so the timing must be tight. Second is to optimize government service. Low efficiency of government services, departments do not coordinate the views of businesses large, poor business environment, it is ... ... Short Board, decide to change. We will continue to deepen reform of the administrative examination and approval system, good digestion, implement the Government canceled, adjustment and devolution of administrative examination and approval matters, strengthen the existing supervision in matters of administrative power, has made it clear to cancel, are not allowed to keep or disguised approval. To do list list of administrative powers and responsibilities 对乙酰氨基酚分散片的制备及质量研究 【摘要】 目的 1.熟悉正交法进行分散片处方工艺的筛选和分散片的制备 2. 掌握分散片的质量检查方法。 方法 对不同崩解剂制成的分散片的崩解时限及分散均匀度的测定，初步筛选出最优崩解剂;以崩解时限为评价指标采用正交设计法来进行对乙酰氨基酚分散片的处方工艺筛选;以外观、崩解时限、脆碎度、溶出度、硬度等为指标，对对乙酰氨基酚的质量进行检查。 结果 最优崩解剂为PVPP,用量为药粉的5%;微晶纤维素为稀释剂;黏合剂为聚乙烯吡咯烷酮(PVP)，用量为药粉的5%;硬度控制在40—70N之间;崩解剂加入方法采用内外加法;颗粒粒度为18目。 结论该工艺中可操作性强、重现性好，其中硬度，脆碎度，崩解时限，溶出度，分散均匀度均合格。但由于筛选时间有限，操作条件失误，分散片的片中差异没有检查，外观不合格。 【关键词】 对乙酰氨基酚 分散片 崩解剂 正交试验 【前言】 分散片系指在水中能迅速崩解并均匀分散的片剂，其主药通常是难溶性的。分散片集片剂和液体制剂的优点，携带服用方便、药物溶出快、生物利用度高等特点。因而将对乙酰氨基酚制成分散片，可增加其吸收度和生物利用度。 分散片处方中常用辅料主要包括:填充剂、崩解剂和黏合剂，其中常用填充剂有:甘露微晶纤维素、可压性淀粉、乳糖等，崩解剂有:交联聚乙烯吡咯烷酮(PPVP)、羧甲基淀粉钠(CMS-Na)、低取代羟丙基纤维素(L-HPC)、微晶纤维素等，黏合剂有:淀粉浆、聚乙烯吡咯烷酮(PVP)、羟丙甲基纤维素。分散片处方组成中崩解剂和黏合剂的种类和用量选择，直接影响制剂在水中的崩解剂分散均匀性。因此，分散片处方组成的确定通常采取以崩解时限为指标，对崩解剂和黏合剂的种类及用量来进行筛选。制备分散片以湿法制粒最为常用，处方中崩解剂的加入方式有内加法、外加法和内、外加法，其加入方式直接影响制剂在水中的崩解及分散均匀性。正交设计法是利用排列整齐的对实验进行整体设计，并通过对实验结果的综合比较和统计分析，评价各因素及其水平对实验结果的影响，从而经少量的实验次数找到较佳的处方工艺条件。对不同崩解剂制成的分散片的崩解时限及分散均匀度的测定，初步筛选出最优崩解剂;以崩解时限为评价指标采用正交设计法来进行对乙酰氨基酚分散片的处方工艺筛选;以外观、崩解时限、脆碎度、溶出度等为指标，对对乙酰氨基酚的质量进行检查。 【实验部分】 一.试剂与仪器 1仪器:蒸发皿，量杯，托盘天平，分析天平;单冲压片机;片剂四用检测仪;冲头;乳钵;量杯;普通天平;尼龙筛(18目);烘箱;崩解时限测定仪，WFZUV-2000型紫外可见分光光度计，RCZ-8A型智能药物溶出仪，脆碎度检查仪， 容量瓶(1000ml，50ml)，微孔滤膜 2 试剂:L-HPC、交联羧甲基纤维素钠、羧甲基淀粉钠 CMS-Na、交联聚乙烯吡咯烷酮 (PPVP)、7%聚乙烯吡咯烷酮 (PVP)(含硫脲)、10%聚乙烯吡咯烷酮 (PVP)(含硫脲)，硬脂酸镁、rAt present, we have formed a "three-three" Park. …… Industrial Park, according to ... ... The instructions of comrade, focus on development needs in the next decade, based on the original, and then extended the 6 square kilometers. Of the Park, to further improve the roads, power supply, communications, water supply and drainage and sewage pipe network and other infrastructure, to achieve full coverage of infrastructure and interconnection with the facilities and raise capacity. Each park to determine 1 leading industries, in particular stone Materials, cans, gloves, through guided, force and other measures to promote the "road company" Park, industrial agglomeration. Currently, to focus on building better ... ... Industrial Park, ... ... Wood Park as the starting area of the industrial park, planners need to take out plan, start construction as soon as possible, undertake in a timely manner ... ... Transfer of the wood industry. This opportunity slip by, so the timing must be tight. Second is to optimize government service. Low efficiency of government services, departments do not coordinate the views of businesses large, poor business environment, it is ... ... Short Board, decide to change. We will continue to deepen reform of the administrative examination and approval system, good digestion, implement the Government canceled, adjustment and devolution of administrative examination and approval matters, strengthen the existing supervision in matters of administrative power, has made it clear to cancel, are not allowed to keep or disguised approval. To do list list of administrative powers and responsibilities 微晶纤维素、60%乙醇溶液。0.1mol/L盐酸溶液 ，0.4g/L氢氧化钠溶液 3 药品:对乙酰氨基酚 二.方法与结果 1 崩解剂的筛选 选取在固体制剂制备中常用崩解剂(CMS-Na,PPVP,L-HPC,交联羧甲基纤维素钠)，进行分散片的制备。处方见1.(1),其中崩解剂用量为3%，粘合剂PVP用量也为3%，制备工艺见1(2)，采用内加法，通过崩解时限测定及分散均匀性评价初步筛选崩解剂种类 (1)分散片处方 对乙酰氨基酚 5g 10%PVP乙醇溶液(含硫脲) 6.8ml 崩解剂 0.68g 微晶纤维素 15.92g 硬脂酸镁 0.22g 共22.5g制成50片 (2)制备 将对乙酰氨基酚、微晶纤维素、崩解剂混合均匀，将含硫脲的10%PVP乙醇溶液加入到上述混合粉末中，混合制成均匀的软材过18目筛制湿颗粒，于50-60?干燥约30min，18目筛整粒，将此颗粒与硬脂酸镁(等量分次加入)混合均匀压片。 (3)分散均匀性及崩解时限 1?的100ml水中，振摇并记录时间，应全部崩解通过20筛。 取分散片置20? (4) 结果 表二 不同崩解剂对分散片的影响结果 CMS-Na(g) 编号 L-HPC(g) 交联羧甲基纤分散均匀性 崩解时限(s) 维素(g) 1 3.0 均匀 90.33 2 3.0 均匀 30.64 3 3.0 均匀 38.00 4 3.0 均匀 65.87 由以上实验数据可知:交联聚乙烯吡咯烷酮 (PPVP)为最优崩解剂 2. 正交设计 (1)根据文献报道，影响分散片质量的主要处方组成及工艺因素，确定采用正交设计法进 行对乙酰氨基酚分散片的处方工艺筛选时，主要考察的因素及水平见下表 (2)分散片处方 对乙酰氨基酚 5g 10%PVP乙醇溶液(含硫脲) 适量 崩解剂 适量 微晶纤维素 适量 rAt present, we have formed a "three-three" Park. …… Industrial Park, according to ... ... The instructions of comrade, focus on development needs in the next decade, based on the original, and then extended the 6 square kilometers. Of the Park, to further improve the roads, power supply, communications, water supply and drainage and sewage pipe network and other infrastructure, to achieve full coverage of infrastructure and interconnection with the facilities and raise capacity. Each park to determine 1 leading industries, in particular stone Materials, cans, gloves, through guided, force and other measures to promote the "road company" Park, industrial agglomeration. Currently, to focus on building better ... ... Industrial Park, ... ... Wood Park as the starting area of the industrial park, planners need to take out plan, start construction as soon as possible, undertake in a timely manner ... ... Transfer of the wood industry. This opportunity slip by, so the timing must be tight. Second is to optimize government service. Low efficiency of government services, departments do not coordinate the views of businesses large, poor business environment, it is ... ... Short Board, decide to change. We will continue to deepen reform of the administrative examination and approval system, good digestion, implement the Government canceled, adjustment and devolution of administrative examination and approval matters, strengthen the existing supervision in matters of administrative power, has made it clear to cancel, are not allowed to keep or disguised approval. To do list list of administrative powers and responsibilities 硬脂酸镁 0.22g 共22.5g制成50片 表三 处方正交设计因素筛选 水平 因素 崩解剂用量A% PVP用量B% 崩解剂加入方法C 1 3 1 内加法 2 5 3 内、外加法 3 7 5 外加法 (2)制备 按照正交实验设计表(见2.4)进行实验安排，崩解剂为PVPP,分别做九组实验，其中当崩解剂加入方式采用内外加法时，内 外加入量各占崩解剂总量的一半。以崩解时限为评价指标筛选出最优处方。 (3)分散均匀性及崩解时限 将分散片置20?1?的100ml水中，振摇并记录时间，应全部崩解通过20号筛。 (4)正交设计表及结果 正交设计实验结果分析 表四 实验 PVPP用量 PVP用量 崩解剂加入方实验结果 硬度(N) 编号 (A%) (B%) 法(C%) (崩解时限 s) 1 A(3.0) (1.0) (内加法) BC33.60 65 111 2 A B(3.0) C(内，外加42.51 60 122 3 A B(5.0) 法) 36.42 55 13 4 A(5.0) B C(外加法) 15.00 50 213 5 A B C 19.33 40 222 ABC6 14.68 45 233 7 A(7.0) B C 21.58 59 311 8 AB C 26.36 55 3 23 BC9 A 13.88 50 331 C 2 K1 37.51 23.39 24.88 K2 16.34 26.88 23.80 K3 20.61 21.66 25.78 Rj 11.20 2.66 0.99 由数据可知RA最大,故因素A对实验结果影响最大,其次是B、C,综合知最优处方为A2B3C2 rAt present, we have formed a "three-three" Park. …… Industrial Park, according to ... ... The instructions of comrade, focus on development needs in the next decade, based on the original, and then extended the 6 square kilometers. Of the Park, to further improve the roads, power supply, communications, water supply and drainage and sewage pipe network and other infrastructure, to achieve full coverage of infrastructure and interconnection with the facilities and raise capacity. Each park to determine 1 leading industries, in particular stone Materials, cans, gloves, through guided, force and other measures to promote the "road company" Park, industrial agglomeration. Currently, to focus on building better ... ... Industrial Park, ... ... Wood Park as the starting area of the industrial park, planners need to take out plan, start construction as soon as possible, undertake in a timely manner ... ... Transfer of the wood industry. This opportunity slip by, so the timing must be tight. Second is to optimize government service. Low efficiency of government services, departments do not coordinate the views of businesses large, poor business environment, it is ... ... Short Board, decide to change. We will continue to deepen reform of the administrative examination and approval system, good digestion, implement the Government canceled, adjustment and devolution of administrative examination and approval matters, strengthen the existing supervision in matters of administrative power, has made it clear to cancel, are not allowed to keep or disguised approval. To do list list of administrative powers and responsibilities 3 成品制备及质量检查 (1) 处方 对乙酰氨基酚 5g PVPP(5%) 1.13g 10%PVP(含硫脲) 11ml 微晶纤维素 15.0g 硬脂酸镁 0.22g 共22.5g制成50片 (2) 制备工艺 将对乙酰氨基酚，可压性淀粉，半剂量崩解剂混合均匀。将含硫脲的10%PVP乙醇溶液加入到上述混合材料粉末中，混合制成均匀的软材，过18目尼龙筛制湿粒，于50-60?干燥约30min，18目筛整粒，将此颗粒和硬脂酸镁、剩余剂量崩解剂混合均匀压片。(AB3C)32 (3) 外观 取压好的分散片,观察其外观:表面部分鼓起，不光滑，色泽均匀，边缘整齐.硬度为55N 。 不合格。 (4)硬度 用片剂四用检测仪测定 55N 合格 (5) 脆碎度 测定方法:将17片分散片用吹风机吹去粉末，用分析天平精密称重，置于脆碎度检查仪圆筒中，转4min(25r/min)，取出，再次吹去粉末，精密称重。 测定结果: 无碎片 左边第一次称量重W:9.45g 第二次称量重W:9.40g 12 减失重量=(W- W)/W × 100%= 0.53% 121 右边第一次量重W:9.07g，第二次称重W:9.06g 12 减失重量=(W- W)/W × 100%=0.11% 121 药典中对对乙酰氨基酚分散片剂脆硬度检查减失重量不得过1%,且不得出现断裂、龟裂及粉碎的片，试验中对酰氨基酚分散片的脆碎度检查合格。 (6) 崩解时限 取分散片置崩解时限测定仪中，开动仪器测定分散片的崩解时限，之全部崩解过筛，记录时间为20s。崩解时限检查合格 (7) 溶出度 测定方法:第一步:取分散片20片，精密称定，求出平均片重。将20片分散片置研钵中研细，精密称取相当于平均片重的片粉置于1000ml容量瓶中，加0.1mol/l HCl溶液适量，振摇，溶解定容至1000ml，摇匀，取5ml微孔滤膜过滤，精密移取1.5ml续滤液置于25ml容量瓶中，用0.4g/l NaOH溶液稀释至刻线，摇匀，以0.4g/lNaOH溶液作参照， *用分光光度计在257nm处测吸光度A值。 第二步:量取1000ml 0.1mol/lHCl溶液放入介质杯中，取6片分散片，精密称定，分rAt present, we have formed a "three-three" Park. …… Industrial Park, according to ... ... The instructions of comrade, focus on development needs in the next decade, based on the original, and then extended the 6 square kilometers. Of the Park, to further improve the roads, power supply, communications, water supply and drainage and sewage pipe network and other infrastructure, to achieve full coverage of infrastructure and interconnection with the facilities and raise capacity. Each park to determine 1 leading industries, in particular stone Materials, cans, gloves, through guided, force and other measures to promote the "road company" Park, industrial agglomeration. Currently, to focus on building better ... ... Industrial Park, ... ... Wood Park as the starting area of the industrial park, planners need to take out plan, start construction as soon as possible, undertake in a timely manner ... ... Transfer of the wood industry. This opportunity slip by, so the timing must be tight. Second is to optimize government service. Low efficiency of government services, departments do not coordinate the views of businesses large, poor business environment, it is ... ... Short Board, decide to change. We will continue to deepen reform of the administrative examination and approval system, good digestion, implement the Government canceled, adjustment and devolution of administrative examination and approval matters, strengthen the existing supervision in matters of administrative power, has made it clear to cancel, are not allowed to keep or disguised approval. To do list list of administrative powers and responsibilities 别投入6个转篮中，调整转速100r/min,计时30min，分别取样5ml用微孔滤膜过滤，分别精密移取1.5ml续滤液置于25ml容量瓶中，用0.4g/l NaOH溶液稀释至刻线，摇匀，分别以0.4g/lNaOH溶液作参照，用分光光度计在257nm处测吸光度A值 测定结果:根据计算公式: * 溶出量%=[(A/ W平均)/(A/W)]*100% 表五 紫外分光光度计测试结果 组号 重量W(g) 吸光度A 溶出量 1 0.46832 0.388 93.48% 2 0.47438 0.438 98.11% 3 0.48084 0.427 94.36% 4 0.46968 0.435 98.41% 5 0.47926 0.451 99.99% 对照 0.47390 0.446 平均溶出量%=(93.48%+98.11%+94.36%+98.41%+99.99%/5=96.87% 药典中规定对乙酰氨基酚分散片剂的溶出度检查规定为30min内药物溶出限度为标示量的80%，实验中测得的平均溶出量为96.87%,，故对乙酰氨基酚分散片剂的溶出度检查合格 4.结果与讨论 通过对对乙酰氨基酚分散片处方中崩解剂筛选试验结果分析选择PVPP作为崩解剂。 分散片由于要达到特定的分散效果(分散片10片，置于100ml水中振摇，在20?1?水中，3min应全部崩解并通过20号筛)，其制备工艺一方面要有好的分散均匀性，另一方面也要达到一般制剂的要求(比如:硬度、脆碎度、外观)，。因此在制备过程中可供选择的范围不大，要去准确控制处方工艺过程。处方和工艺充分考虑了各种因素的结果，制备出的分散片分散均匀性、硬度、脆碎度、外观均较好。通过正交试验比较研究得出的最优处方为A2B3C2. 崩解剂的加入方法应该是内、外加法崩解时限最小 对乙酰氨基酚分散片外观检查不合格，是因为干燥后的颗粒放置空气中的时间过长,其吸潮引起分散片表面有鼓起,不光滑.本实验应一个人独立完成，但是由于实验条件与实验时间的限制，需要大家配合完成实验，在这个过程中，每一个人所制的软材湿度，粒度大小，压片的硬度，还有测定分散均匀性时振摇的力度与速度均不同，造成实验数据偏差，实验结果不精确。 5.结论 实验筛选出的最优崩解剂PVPP，最佳处方工艺为崩解剂PVPP,用量为药粉重的5.0%，粘合rAt present, we have formed a "three-three" Park. …… Industrial Park, according to ... ... The instructions of comrade, focus on development needs in the next decade, based on the original, and then extended the 6 square kilometers. Of the Park, to further improve the roads, power supply, communications, water supply and drainage and sewage pipe network and other infrastructure, to achieve full coverage of infrastructure and interconnection with the facilities and raise capacity. Each park to determine 1 leading industries, in particular stone Materials, cans, gloves, through guided, force and other measures to promote the "road company" Park, industrial agglomeration. Currently, to focus on building better ... ... Industrial Park, ... ... Wood Park as the starting area of the industrial park, planners need to take out plan, start construction as soon as possible, undertake in a timely manner ... ... Transfer of the wood industry. This opportunity slip by, so the timing must be tight. Second is to optimize government service. Low efficiency of government services, departments do not coordinate the views of businesses large, poor business environment, it is ... ... Short Board, decide to change. We will continue to deepen reform of the administrative examination and approval system, good digestion, implement the Government canceled, adjustment and devolution of administrative examination and approval matters, strengthen the existing supervision in matters of administrative power, has made it clear to cancel, are not allowed to keep or disguised approval. To do list list of administrative powers and responsibilities 剂聚乙烯吡咯烷酮(PVP)用量为药粉重的5.0%，微晶纤维素为填充剂,硬酯酸镁为润湿剂,硫脲为抗氧剂,崩解剂的加入方法为内外加法.但由于实验中条件的限制和操作程中存在失误,部分质量检查项目没有检查包括片中差异，但是已检查的项目中除外观其余的硬度，脆碎度，崩解时限，溶出度，分散均匀度均合格。 【参考文献】 1. 凌春生.药剂学实验指导.开封:河南大学药学院药剂教研室，2007年12月. 2. 崔福德.药剂学[M].第6版.北京:人民卫生出版社，2008. 3. 药典 中华人民共和国食品药品监督局(2010版). 4. 罗明生，高天惠.药剂辅料大全[M].成都:四川科学技术出版社，1995. 5. 邹立家.药剂学.普通高等专科教育规划教材. 6. WS1-(X-010)-200IZ,国家药品[S]. 7. 毕殿洲.药剂学[M].第四版.人民卫生出版社，1999. rAt present, we have formed a "three-three" Park. …… Industrial Park, according to ... ... The instructions of comrade, focus on development needs in the next decade, based on the original, and then extended the 6 square kilometers. Of the Park, to further improve the roads, power supply, communications, water supply and drainage and sewage pipe network and other infrastructure, to achieve full coverage of infrastructure and interconnection with the facilities and raise capacity. Each park to determine 1 leading industries, in particular stone Materials, cans, gloves, through guided, force and other measures to promote the "road company" Park, industrial agglomeration. Currently, to focus on building better ... ... Industrial Park, ... ... Wood Park as the starting area of the industrial park, planners need to take out plan, start construction as soon as possible, undertake in a timely manner ... ... Transfer of the wood industry. This opportunity slip by, so the timing must be tight. Second is to optimize government service. Low efficiency of government services, departments do not coordinate the views of businesses large, poor business environment, it is ... ... Short Board, decide to change. We will continue to deepen reform of the administrative examination and approval system, good digestion, implement the Government canceled, adjustment and devolution of administrative examination and approval matters, strengthen the existing supervision in matters of administrative power, has made it clear to cancel, are not allowed to keep or disguised approval. To do list list of administrative powers and responsibilities