欧洲药典第六版 2.4.8
头孢曲松钠欧洲药典6.0版
EUROPEAN PHARMACOPOEIA 6.0CeftriaxonesodiumC.(6R ,7R )-2-carboxy-8-oxo-3-(pyridiniomethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-aminiumdichloride,D.(6R ,7R )-7-[[(Z )-2-[[2-(1,1-dimethylethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-2-[2-[(triphenylmethyl)amino]thiazol-4-yl]acetyl]amino]-8-oxo-3-(pyridiniomethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate,E.(6R ,7R )-7-[[(Z )-2-(2-ammoniothiazol-4-yl)-2-[[2-(1,1-dimethylethoxy)-1,1-dimethyl-2-oxoethoxy]imino]acetyl]amino]-8-oxo-3-(pyridiniomethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate chloride,F.pyridine.01/2008:0991CEFTRIAXONE SODIUMCeftriaxonum natricum C 18H 16N 8Na 2O 7S 3,31/2H 2O M r 662[104376-79-6]DEFINITIONDisodium (6R ,7R )-7-[[(2Z )-(2-aminothiazol-4-yl)(methoxyimino)acetyl]amino]-3-[[(2-methyl-6-oxido-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)sulphanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 3.5hydrate.Semi-synthetic product derived from a fermentation product.Content :96.0per cent to 102.0per cent (anhydrous substance).CHARACTERSAppearance :almost white or yellowish,slightly hygroscopic,crystalline powder.Solubility :freely soluble in water,sparingly soluble in methanol,very slightly soluble in anhydrous ethanol.IDENTIFICATIONA.Infrared absorption spectrophotometry (2.2.24).Comparison :ceftriaxone sodium CRS .B.It gives reaction (a)of sodium (2.3.1).TESTSSolution S .Dissolve 2.40g in carbon dioxide-free water R and dilute to 20.0ml with the same solvent.Appearance of solution .The solution is clear (2.2.1)and not more intensely coloured than reference solution Y 5or BY 5(2.2.2).Dilute 2ml of solution S to 20ml with water R .pH (2.2.3):6.0to 8.0for solution S.Specific optical rotation (2.2.7):−155to −170(anhydrous substance).Dissolve 0.250g in water R and dilute to 25.0ml with the same solvent.Related substances .Liquid chromatography (2.2.29).Test solution .Dissolve 30.0mg of the substance to be examined in the mobile phase and dilute to 100.0ml with the mobile phase.Reference solution (a).Dissolve 30.0mg of ceftriaxone sodium CRS in the mobile phase and dilute to 100.0ml with the mobile phase.Reference solution (b).Dissolve 5.0mg of ceftriaxonesodium CRS and 5.0mg of ceftriaxone impurity A CRS in the mobile phase and dilute to 100.0ml with the mobilephase.Reference solution (c).Dilute 1.0ml of the test solution to 100.0ml with the mobile phase.Column :—size :l =0.25m,Ø=4.6mm;—stationary phase :octadecylsilyl silica gel forchromatography R (5µm).Mobile phase :dissolve 2.0g of tetradecylammoniumbromide R and 2.0g of tetraheptylammonium bromide R ina mixture of 440ml of water R ,55ml of 0.067M phosphatebuffer solution pH 7.0R ,5.0ml of citrate buffer solutionpH 5.0prepared by dissolving 20.17g of citric acid R in 800ml of water R ,adjusting to pH 5.0with strong sodium hydroxide solution R and diluting to 1000.0ml with water R ,and 500ml of acetonitrile R .Flow rate :1.5ml/min.Detection :spectrophotometer at 254nm.Injection :20µl of the test solution and reference solutions (b)and (c).Run time :twice the retention time of ceftriaxone.System suitability :reference solution (b):—resolution :minimum 3.0between the peaks due to ceftriaxone and impurity A.Limits :—any impurity :not more than the area of the principal peak in the chromatogram obtained with reference solution (c)(1.0per cent);General Notices (1)apply to all monographs and other texts1461Cefuroxime axetil EUROPEAN PHARMACOPOEIA6.0—total :not more than 4times the area of the principal peak in the chromatogram obtained with reference solution (c)(4.0per cent);—disregard limit :0.1times the area of the principal peak in the chromatogram obtained with reference solution (c)(0.1per cent).N,N -Dimethylaniline (2.4.26,Method B ):maximum 20ppm.2-Ethylhexanoic acid (2.4.28):maximum 0.8per cent m/m .Water (2.5.12):8.0per cent to 11.0per cent,determinedon 0.100g.Bacterial endotoxins (2.6.14):less than 0.08IU/mg,if intended for use in the manufacture of parenteral dosage forms without a further appropriate procedure for the removal of bacterial endotoxins.ASSAYLiquid chromatography (2.2.29)as described in the test for related substances with the following modification.Injection :test solution and reference solution (a).Calculate the percentage content of C 18H 16N 8Na 2O 7S 3from the declared content of ceftriaxone sodium CRS .STORAGEIn an airtight container protected from light.If the substance is sterile,store in a sterile,airtight,tamper-proof container.IMPURITIESA.(6R ,7R )-7-[[(2E )-(2-aminothiazol-4-yl)(methoxy-imino)acetyl]amino]-3-[[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)sulphanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid ((E)-isomer),B.(5a R ,6R )-6-[[(2Z )-(2-aminothiazol-4-yl)(methoxy-imino)acetyl]amino]-5a,6-dihydro-3H ,7H -azeto-[2,1-b ]furo[3,4-d ][1,3]thiazine-1,7(4H)-dione,C.2-methyl-3-sulphanyl-1,2-dihydro-1,2,4-triazine-5,6-dione, D.S -benzothiazol-2-yl (2Z )-(2-aminothiazol-4-yl)(methoxyimino)thioacetate,E.(6R ,7R )-7-amino-3-[[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)sulphanyl]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.01/2008:1300corrected 6.0CEFUROXIME AXETIL CefuroximumaxetiliC 20H 22N 4O 10S M r 510.5[64544-07-6]DEFINITIONMixture of the 2diastereoisomers of (1RS )-1-(acetyloxy)ethyl (6R ,7R )-3-[(carbamoyloxy)methyl]-7-[[(Z )-2-(furan-2-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylate.Semi-synthetic product derived from a fermentation product.Content :96.0per cent to 102.0per cent (anhydrous substance).CHARACTERSAppearance :white or almost white powder.Solubility :slightly soluble in water,soluble in acetone,in ethyl acetate and in methanol,slightly soluble in ethanol (96per cent).IDENTIFICATIONA.Infrared absorption spectrophotometry (2.2.24).Comparison :cefuroxime axetil CRS .B.Examine the chromatograms obtained in the assay.1462See the information section on general monographs (cover pages)。
欧洲药典-沙美特罗
EUROPEAN PHARMACOPOEIA 7.0Salmeterolxinafoate Chlorides (2.4.4):maximum 100ppm.Dilute 10mL of solution S to 15mL with water R .Sulfates :maximum 200ppm.Dissolve 1.0g in 5mL of dimethylformamide R and add 4mL of water R .Mix thoroughly.Add 0.2mL of dilute hydrochloric acid R and 0.5mL of a 25per cent m/m solution of barium chloride R .After 15min any opalescence in the solutionis notmore intense than that in a standard prepared as follows:to 2mL of sulfate standard solution (100ppm SO 4)R add 0.2mLof dilute hydrochloric acid R ,0.5mL of a 25per cent m/m solution of barium chloride R ,3mL of water R and 5mL of dimethylformamide R .Heavy metals (2.4.8):maximum 20ppm.Dissolve 2.0g in 15mL of ethanol (96per cent)R and add 5mLof water R .12mL of the solution complies with test B.Prepare the reference solution using lead standard solution (2ppm Pb)prepared by diluting lead standard solution (100ppm Pb)R with a mixture of 5volumes of water R and 15volumes of ethanol (96per cent)R .Loss on drying (2.2.32):maximum 0.5per cent,determined on1.000g by drying in a desiccator.Sulfated ash (2.4.14):maximum 0.1per cent,determined on 2.0g.ASSAY Dissolve 0.120g in 30mL of ethanol (96per cent)R and add20mL of water R .Titrate with 0.1M sodium hydroxide,using 0.1mL of phenol red solution R as indicator.1mL of 0.1M sodium hydroxide is equivalent to 13.81mg ofC 7H 6O 3.STORAGE Protected from light.IMPURITIES Specified impurities:A,B,C.A.R =H:4-hydroxybenzoic acid,B.R =CO 2H:4-hydroxyisophthalicacid,C.phenol.01/2008:1765SALMETEROL XINAFOATE Salmeterolixinafoas C 36H 45NO 7M r 604[94749-08-3]DEFINITION (1RS )-1-[4-Hydroxy-3-(Hydroxymethyl)phenyl]-2-[[6-(4-phenylbutoxy)hexyl]amino]ethanol 1-hydroxynaphthalene-2-carboxylate.Content :97.0per cent to 102.0per cent (anhydrous substance).CHARACTERSAppearance :white or almost white powder.Solubility:practically insoluble in water,soluble in methanol,slightly soluble in anhydrous ethanol.IDENTIFICATION Infrared absorption spectrophotometry (2.2.24).Comparison :salmeterol xinafoate CRS .TESTSRelated substances .Liquid chromatography (2.2.29).Protect the solutions from light.Solvent mixture :acetonitrile R ,water R (50:50V/V ).Testsolution .Dissolve 50.0mg of the substance to be examined inthe solvent mixture and dilute to 10.0mL with the solvent mixture.Reference solution (a).Dissolve 11mg of salmeterol xinafoate for system suitability CRS (salmeterol containing impurities Eand G)in the solvent mixture and dilute to 2mL with the solvent mixture.Referencesolution (b).Dilute 1.0mL of the testsolution to 100.0mL with the solvent mixture.Dilute 1.0mL of this solution to 10.0mL with the solvent mixture.Column :—size :l =0.15m,Ø=4.6mm,—stationary phase :octadecylsilyl silica gel forchromatography R (5μm).Mobile phase :—mobile phase A:mix 24volumes of a 7.71g/L solutionof ammonium acetate R with 24volumes of a 28.84g/Lsolution of sodium dodecyl sulfate R and adjust to pH 2.7with glacial acetic acid R ;mix with 52volumes of acetonitrile R ;—mobile phase B :acetonitrile R ;Time (min)Mobile phase A (per cent V/V )Mobile phase B(per cent V/V )0-16100016-36100→300→7036-45307045-5030→10070→0Flow rate :2mL/min.Detection :spectrophotometer at 278nm.Injection :20μL;inject the solvent mixture as a blank solution.Relative retention with reference to salmeterol (retentiontime =about 13min):xinafoic acid =about 0.2;impurity A =about 0.3;impurity B =about 0.5;impurity C =about 0.7;impurity D =about 0.8;impurity E =about 0.9;impurity F =about 1.6;impurity G =about 2.7.System suitability :reference solution (a):—peak-to-valley ratio :minimum 10,where H p =height abovethe baseline of the peak due to impurity E and H v =height above the baseline of the lowest point of the curve separatingthis peak from the peak due to salmeterol,—the chromatogram obtained is similar to the chromatogramsupplied with salmeterol xinafoate for system suitability CRS .Limits :—impurity D :not more than 3times the area of the principalpeak in the chromatogram obtained with reference solution (b)(0.3per cent),—impurities A,F,G :for each impurity,not more than twice the area of the principal peak in the chromatogram obtained with reference solution (b)(0.2per cent),General Notices (1)apply to all monographs and other texts 2885Salmon oil,farmed EUROPEAN PHARMACOPOEIA7.0—impurities B,C,E :for each impurity,not more than the area of the principal peak in the chromatogram obtained with reference solution (b)(0.1per cent),—any other impurity :for each impurity,not more than the area of the principal peak in the chromatogram obtained with reference solution (b)(0.1per cent),—total :not more than 9times the area of the principal peak in the chromatogram obtained with reference solution (b)(0.9per cent),—disregard limit :0.5times the area of the principal peak in thechromatogram obtained with reference solution (b)(0.05per cent);disregard the peak due to xinafoic acid andany peaks due to the blank.Water (2.5.12):maximum 0.5per cent,determined on 1.000g.Dissolve the sample with 30mL of anhydrous methanol R .Sulfated ash (2.4.14):maximum 0.1per cent,determined on1.0g.ASSAY Liquid chromatography (2.2.29).Test solution .Dissolve 12.50mg of the substanceto be examined in the mobile phase and dilute to 50.0mL with themobile phase.Reference solution (a).Dissolve 12.50mgof salmeterol xinafoate CRS in the mobile phase and dilute to 50.0mL withthe mobile phase.Reference solution (b).Dilute 1mL of reference solution (a)described in the test for related substances to 20mL with the mobile phase.Column :—size :l =0.15m,Ø=4.6mm,—stationary phase :octadecylsilyl silica gel for chromatography R (5μm).Mobile phase:mix 24volumes of a 7.71g/Lsolutionof ammonium acetate R with 24volumes of a 28.84g/L solution of sodium dodecyl sulfate R and adjust to pH 2.7with glacial acetic acid R .Mix with 52volumes of acetonitrile R .Flow rate :2mL/min.Detection :spectrophotometer at 278nm.Injection :20μL.Run time :until complete elution of the peak due to salmeterol(about 16min).System suitability :reference solution (b):—peak-to-valley ratio :minimum10,where H p =height abovethe baseline of the peak due to impurity E and H v =height above the baseline of the lowest point of the curve separating this peak from the peak due to salmeterol.The stationary phase may be regenerated using the gradient described under the test for related substances.Calculate the percentage content of C 36H 45NO 7using the chromatogram obtained with reference solution (a)and the declared content of C 36H 45NO 7in salmeterol xinafoate CRS .STORAGE Protected from light.IMPURITIES Specified impurities:A,B,C,D,E,F,G.A.R =[CH 2]4-C 6H 5,R ′=OH:(1RS )-1-[4-hydroxy-3-(hydroxymethyl)phenyl]-2-[(4-phenylbutyl)amino]ethanol, B.R =[CH 2]6-O-[CH 2]2-C 6H 5,R ′=OH:(1RS )-1-[4-hydroxy-3-(hydroxymethyl)phenyl]-2-[[6-(2-phenylethoxy)hexyl]amino]ethanol,C.R =[CH 2]6-O-[CH 2]3-C 6H 5,R ′=OH:(1RS )-1-[4-hydroxy-3-(hydroxymethyl)phenyl]-2-[[6-(3-phenylpropoxy)hexyl]amino]ethanol,F.R =[CH 2]6-O-[CH 2]4-C 6H 5,R ′=H:(1RS )-1-(4-hydroxy-3-methylphenyl)-2-[[6-(4-phenylbutoxy)hexyl]amino]ethanol,D.1-[4-[2-hydroxy-2-[4-hydroxy-3-(hydroxy-methyl)phenyl]ethoxy]-3-(hydroxymethyl)phen-yl]-2-[[6-(3-phenylbutoxy)hexyl]amino]ethanol,E.1-[4-hydroxy-3-(hydroxymethyl)phenyl]-2-[[6-(1-methyl-3-phenylpropoxy)hexyl]amino]ethanol,G.1-[4-hydroxy-3-[[[2-hydroxy-2-[4-hydroxy-3-(hydroxy-methyl)phenyl]ethyl][6-(4-phenylbutoxy)hexyl]amino]meth-yl]phenyl]-2-[[6-(4-phenylbutoxy)hexyl]amino]ethanol.01/2008:1910SALMON OIL,FARMEDSalmonis domestici oleumDEFINITIONPurified fatty oil obtained from fresh farmed Salmo salar .The positional distribution (β(2)-acyl)is 60-70per cent for cervonic (docosahexaenoic)acid (C22:6n-3;DHA),25-35per cent fortimnodonic (eicosapentaenoic)acid (C20:5n-3;EPA)and40-55per cent for moroctic acid (C18:4n-3).Content :—sumof the contents of EPA and DHA (expressed as triglycerides):10.0per cent to 28.0per cent.Authorised antioxidants in concentrations not exceeding the levels specified by the competent authority may be added.PRODUCTIONThe fish shall only be given feed with a composition that is in accordance with the relevant EU or other applicable regulations.The oil is produced by mechanical expression of fresh rawmaterials,either from the whole fish,or fish where the filletshave been removed,at a temperature not exceeding100°C,and without using solvents.After centrifugation,solidsubstances may be removed from the oil by cooling and filtering (winterisation).2886See the information section on general monographs (cover pages)。
欧洲药典重金属检测
2.4.8 重金属下述方法需要使用硫代乙酰胺试剂。
作为另一种选择，硫化钠溶液（0.1ml）也常常适用。
由于各论中所述测试是使用硫代乙酰胺试剂研发出来的，如需用硫化钠溶液替代，需要包括方法A、方法B和方法H监测溶液，由测试规定的待测物的量进行配制，其已经加入了制备对照溶液规定量的铅标准溶液。
监测溶液至少要与对照溶液一样深，否则测试是无效的。
方法A供试溶液：12ml待测物水溶液。
对照溶液（标准）：10ml规定的标准铅溶液（1ppm or 2ppm Pb）和2ml的待测液混合。
空白溶液：10ml的水和2ml的测试溶液混合。
向每种溶液中，加入2ml pH为3.5的缓冲溶液。
混合后加1.2ml的硫代乙酰胺试液，立即混合。
2分钟后目测。
系统适用性：相较于空白溶液，对照溶液呈浅棕色结果：供试溶液的棕色不深于对照溶液。
若结果难以判断，进行膜过滤（孔径0.45μm）。
使用中等强度且恒定的压力缓慢且均匀地过滤。
比较不同溶液在过滤器上产生的斑点。
方法B供试溶液：用含最少量水的溶剂（例如含15％水的二氧杂环乙烷或含15％水的丙酮）溶解成12ml待测液。
对照溶液（标准）：10ml规定的铅标准溶液（1ppm or 2ppm Pb），加入2ml的待测液。
用待测物所用溶剂稀释100ppm Pb的铅标准溶液至1或2ppm Pb。
空白溶液：10ml待测物所用溶剂和2ml的待测溶液混合。
向每种溶液中，加入2ml pH为3.5的缓冲溶液。
混合后加1.2ml的硫代乙酰胺试液，立即混合。
2分钟后目测。
系统适用性：相较于空白溶液，对照溶液呈浅棕色结果：供试溶液的棕色不深于对照溶液。
若结果难以判断，进行膜过滤（孔径0.45μm）。
使用中等强度且恒定的压力缓慢且均匀地过滤。
比较不同溶液在过滤器上产生的斑点。
方法C供试溶液：规定量（不超过2g）的待测物质置于坩埚内，加4ml 250g/l硫酸镁的稀硫酸溶液。
玻璃棒搅拌混和，小心加热。
若混合物仍为液体，则在水浴中蒸发使其干燥。
国外药典介绍
欧洲药典增补版
• 欧洲药典第8版包括两个基本卷，于2013年7月出版发行，以后在每次欧洲
药典委员会全会做出决定后，通过非累积增补本更新，每年出3个增补本。第 8版累计共有8个非累积增补本（8.1～8.8）。 各增补版的出版日期及执行的日期。·
欧洲各册内容介绍
第一卷
各论举例、前言、介绍、总目录、第8版内容简介（包括新增内容、 修订内容和更正内容）
欧洲各册内容介绍第一卷各论举例前言介绍总目录第8版内容简介包括新增内容修订内容和更正内容版内容简介包括新增内容修订内容和更正内容genaralnotice凡例分析方法通论包装材料及包装试剂genaraltext通则各论通则剂型各论人用疫苗各论兽用疫苗各论人用免疫血通则各论通则剂型各论人用疫苗各论兽用疫苗各论人用免疫血清各论兽用免疫血清各论放射制剂及放射制剂起始物各论人20151215清各论兽用免疫血清各论放射制剂及放射制剂起始物各论人用手术缝合线各论兽用手术缝合线各论草药及草药制剂各论顺势疗法制剂各论用手术缝合线各论兽用手术缝合线各论草药及草药制剂各论顺势疗法制剂各论第二卷各论举例各论按字母的索引页总索引每卷均有侧面黑色索引标示各论举例各论按字母的索引页总索引每卷均有侧面黑色索引标示欧洲各册内容介绍增补举例
USP–NF 的不断 修订
修订公告 IRA拟议的修订 说明
勘误表
2019/12/16
美国药典的修订
USP–NF 不断进行修订。 修订包括 USP–NF 年度修订和每年两 次增补，以及 USP 网站上的加速修订。 USP 使用加速修订过程 加快修订美国药典–国家处方集 (USP–NF)。加速修订包括修订公 告、临时修订声明 (IRA) 和勘误表。 是 USP 最快的修订途径，可取代在 USP–NF 及其增补（印刷版 和在线版）中发布的标准。 在 USP 网站上发布的修订公告指示 其正式日期和纳入正式出版物中的日期。 IRA 在 PF 中发布，征求公众意见期为 90 天。 在意见（如果有） 通过审查并且 IRA 得到相关专家委员会的批准后，最终 IRA 将发 布在 USP 网站上。 与修订公告一样，IRA 可取代在印刷版和在线 版的 USP–NF 及其增补中发布的标准。 IRA 被纳入下一个可用的 USP–NF 或增补中。 是指在 USP–NF 或其增补中发布的文字有误，不能准确地反映专 家委员会批准的预期要求。 勘误表发布在网站上，并立即成为正 式版本。 勘误表被纳入下一个可用的正式出版物中。
欧洲药典——精选推荐
欧洲药典◇欧洲药典8为欧洲药典最新版本;◇ 2013年7⽉出版;◇ 2014年1⽉⽣效。
欧洲药典第8版包括两个基本卷，于2013年7⽉出版发⾏，以后在每次欧洲药典委员会全会做出决定后，通过⾮累积增补本更新，每年出3个增补本。
第8版累计共有8个⾮累积增补本（8.1～8.8）。
各增补版的出版⽇期及执⾏的⽇期。
最初的两卷包括第7版完整的内容，以及欧洲药典委员会在2012年12⽉全会上通过或修订的内容，共收载了2224个个论，345个含插图或⾊谱图的总论，以及2500种试剂的说明。
变化的内容（插⼊或删除的内容）在页边标注出⾃2014年1⽉起，在欧洲药典成员国，包括欧盟国家，将执⾏第8版并取代第7版。
第7版⾄12⽉31⽇都是有效的。
欧洲药典有英⽂版与法⽂版，英语与法语是欧洲委员会的官⽅语⾔。
欧洲药典有印刷版、USB闪存版和在线版。
其西班⽛⽂版正在翻译之中，将来包括在在线版中，不再另收取费⽤。
欧洲药典：⼀部药品与药⽤物质的标准欧洲药典是欧洲药品质量控制的标准。
已有多项法律⽂件使欧洲药典成为法定标准：2009年经36个欧洲国家和欧盟批准的编撰欧洲药典协议；关于⼈⽤或兽⽤药品的欧盟指令2001/82/EC、2001/83/EC（修正案）和2003/63/EC，维持了欧洲药典对在欧洲上市药品的强制执⾏性。
这些标准规定了药品、⽣产⽤原材料与合成⽤中间体成份的定性、定量和所⽤的检验项⽬。
所有药品、药⽤物质⽣产企业在欧洲销售或使⽤其产品时，都必须遵循欧洲药典标准。
欧洲药典的内容具有法律约束⼒，由⾏政管理或司法部门强制要求符合欧洲药典。
成员国的国家当局必须采⽤欧洲药典，必要时可替代相同物质国家标准中的个论。
欧洲药典的内容包括活性物质、辅料、化学、动物、⼈或植物来源的药⽤物质或制品、顺势疗法制剂和顺势疗法原料、抗⽣素，以及制剂和容器等。
欧洲药典还适⽤于⽣物制品、⾎液和⾎浆制品、疫苗和放射药品。
欧洲药典8 EP8相关内容Index 8.0 EP8.0索引Index 8.3 EP8.3索引Index 8.5 EP8.5索引Index 8.6 EP8.6索引欧洲药典8.6内容变更NEW TEXTSThe texts below appear for the first time in the European Pharmacopoeia. They will be implemented on 1 January 2016 at the latest.MONOGRAPHSRadiopharmaceutical preparations and starting materials for radiopharmaceutical preparations Copper tetramibi tetrafluoroborate for radiopharmaceuticalpreparations (2547)Herbal drugs and herbal drug preparationsAnemarrhena asphodeloides rhizome (2661)Hamamelis bark (2532)Indigo plant leaf (2727)Homoeopathic preparationsBelladonna for homoeopathic preparations (2489)Petroleum rectificatum for homoeopathic preparations (2683)Staphysagria for homoeopathic preparations (2289)MonographsExemestane (2766)Nicorandil (2332)Pirfenidone (2856)Sodium selenite (2740)Solifenacin succinate (2779)Somatropin solution for injection (2370)REVISED TEXTSThe texts below have been technically revised since their last publication. They will be implemented on 1 January 2016.GENERAL CHAPTERS2.2.4. Approximate pH of solutions2.2.19. Amperometric titration2.2.20. Potentiometric titration2.2.34. Thermal analysis2.2.36. Potentiometric determination of ionic concentration using ion-selective electrodes 2.4.29. Composition of fatty acids in oils rich in omega-3 acids2.5.5. Peroxide value2.5.32. Water: micro determination2.9.3. Dissolution test for solid dosage forms2.9.40. Uniformity of dosage units4. Reagents (new, revised, corrected)5.2.4. Cell cultures for the production of veterinary vaccines5.8. Pharmacopoeial harmonisation5.22. Names of herbal drugs used in traditional Chinese medicineMONOGRAPHSVaccines for veterinary use Brucellosis vaccine (live) (Brucella melitensis Rev. 1 strain) for veterinary use (0793)Radiopharmaceutical preparations and starting materialsfor radiopharmaceutical preparationsPentetate sodium calcium for radiopharmaceuticalpreparations (2353)Technetium (99mTc) medronate injection (0641)Herbal drugs and herbal drug preparationsBenzoin, Siam (2158)Bilberry fruit, dried (1588)Bilberry fruit, fresh (1602)Centella (1498)Fresh bilberry fruit dry extract, refined and standardised (2394)Ginseng (1523)Java tea (1229)Homoeopathic preparationsMethods of preparation of homoeopathic stocks and potentisation (2371)MonographsAluminium phosphate, hydrated (1598)Amidotrizoic acid dihydrate (0873)Amiloride hydrochloride dihydrate (0651)Amlodipine besilate (1491)Anticoagulant and preservative solutions for human blood (0209)Aprotinin (0580)Aprotinin concentrated solution (0579)Bromhexine hydrochloride (0706)Buserelin (1077)Carbomers (1299)Carnauba wax (0597)Chymotrypsin (0476)Crospovidone (0892)Demeclocycline hydrochloride (0176)Dihydralazine sulfate, hydrated (1310)Diphenhydramine hydrochloride (0023)Dithranol (1007)Doxapram hydrochloride (1201)Filgrastim concentrated solution (2206)Fluticasone propionate (1750)Fructose (0188)Fulvestrant (2443)Galactose (1215)Glimepiride (2223)Glucose, anhydrous (0177)Glucose monohydrate (0178)Hexylresorcinol (1437)Human coagulation factor IX (rDNA) concentrated solution (2522) Hypromellose (0348)Iopanoic acid (0700)Ioxaglic acid (2009)Isoleucine (0770)Lactose, anhydrous (1061)Lactose monohydrate (0187)Leucine (0771)Lysine hydrochloride (0930)Methionine (1027)Methylcellulose (0345)Methylprednisolone acetate (0933)Methylprednisolone hydrogen succinate (1131) Methylthioninium chloride (1132)Naftidrofuryl hydrogen oxalate (1594)Nicotinamide (0047)Orphenadrine citrate (1759)Orphenadrine hydrochloride (1760)Oxeladin hydrogen citrate (1761)Oxolinic acid (1353)Pancreas powder (0350)Phenazone (0421)Phentolamine mesilate (1138)Polysorbate 80 (0428)Potassium hydroxide (0840)Povidone, iodinated (1142)Propylene glycol dicaprylocaprate (2122)Quinidine sulfate (0017)Quinine hydrochloride (0018)Quinine sulfate (0019)Risedronate sodium 2.5-hydrate (2572)Rivastigmine hydrogen tartrate (2630)Sodium amidotrizoate (1150)Sodium hydroxide (0677)Sodium nitroprusside (0565)Sodium selenite pentahydrate (1677)Spirapril hydrochloride monohydrate (1766)Sucrose (0204)Sugar spheres (1570)Sulfacetamide sodium (0107)Theophylline-ethylenediamine hydrate (0301)Thiamine hydrochloride (0303)Thiamine nitrate (0531)Thiamphenicol (0109)Tribenoside (1740)Trypsin (0694)CORRECTED TEXTSThe texts below have been corrected and are republished in their entirety. These corrections are to be taken into account from the publication date of Supplement 8.6 (1 July 2015), unless otherwise indicated.GENERAL CHAPTERS2.4.22. Composition of fatty acids by gas chromatography2.5.1. Acid value2.7.14. Assay of hepatitis A vaccine2.8.13. Pesticide residues5.7. Table of physical characteristics of radionuclides mentioned in the European PharmacopoieaMONOGRAPHSRadiopharmaceutical preparations and starting materials for radiopharmaceutical preparations Gallium (68Ga) edotreotide injection (2482)MonographsCimetidine (0756)Cimetidine hydrochloride (1500)Flucytosine (0766)Goserelin (1636)Human antithrombin III concentrate (0878)(1)Insulin, bovine (1637)Insulin, human (0838)Insulin, porcine (1638)Insulin preparations, injectable (0854)Isomalt (1531)Miconazole nitrate (0513)Nitric acid (1549)Oxaliplatin (2017)Polyoxypropylene stearyl ether (2602)HARMONISED TEXTSThe texts below have undergone pharmacopoeial harmonisation (see chapter 5.8. Pharmacopoeial harmonisation).GENERAL CHAPTERS2.2.34. Thermal analysis2.9.3. Dissolution test for solid dosage forms2.9.40. Uniformity of dosage unitsMONOGRAPHSMonographsCrospovidone (0892)Glucose, anhydrous (0177)Glucose monohydrate (0178)Hypromellose (0348)Methylcellulose (0345)Polysorbate 80 (0428)TEXTS WHOSE TITLE HAS CHANGEDThe titles of the following texts have been changed in Supplement 8.6.GENERAL CHAPTERS2.2.4. Approximate pH of solutions (previously Relationship between reaction of solution, approximate pH and colour of certain indicators)MONOGRAPHSMonographsAmiloride hydrochloride dihydrate (0651) (previously Amiloride hydrochloride)DELETED TEXTSThe following texts are deleted as of 1 January 2016.MONOGRAPHSImmunosera for veterinary useClostridium novyi alpha antitoxin for veterinary use (0339)Clostridium perfringens beta antitoxin for veterinary use (0340)Clostridium perfringens epsilon antitoxin for veterinary use (0341)The following text is deleted as of 1 April 2015.MONOGRAPHSMonographsLiquorice ethanolic liquid extract, standardised (1536)下载PDF格式订购欧洲药典版本货期⽣效⽇期价格欧洲药典8[2卷]及增补1、2 [印刷/英⽂]现货2014年1⽉￥4950.00欧洲药典8 增补3、增补4、增补5 [印刷/英⽂]现货2014年4⽉￥4950.00欧洲药典8.3、8.4、8.5 [U盘/英⽂/含8.0-8.2内容]现货2014年4⽉￥4950.00欧洲药典8.6、8.7、8.8 [U盘/英⽂/含8.0-8.5内容]现货2016年1⽉￥4950.00。
欧洲药典 胰蛋白酶
Trypsin EUROPEAN PHARMACOPOEIA7.0Static head-space conditions which may be used:—equilibration temperature:80°C,—equilibration time:45min,—transfer line temperature:110°C,—pressurisation time:2min,—injection time:12s.Temperature:Time (min)Temperature(°C)Column0-5405-1840→200 Injection port150 Detector250 Detection:flame ionisation.Injection:1.0mL.The peak due to ethylene oxide is identified by injecting solutions of ethylene oxide of increasing concentration. Determine the content of ethylene oxide(ppm)in the substance to be examined using the following expression:A 1=area of the peak due to ethylene oxide in the chromatogram obtained with the test solution,A 2=area of the peak due to ethylene oxide in the chromatogram obtained with the reference solution,m1=mass of ethylene oxide in the reference solution,in micrograms,m2=mass of the substance to be examined in the test solution,in grams,m3=mass of the substance to be examined in the reference solution,in grams.Limit:—ethylene oxide:maximum1ppm.Heavy metals(2.4.8):maximum20ppm.1.0g complies with test F.Prepare the reference solution using 2mL of lead standard solution(10ppm Pb)R.Loss on drying(2.2.32):maximum5.0per cent,determined on 1.000g by drying in an oven at105°C for4h.Sulfated ash(2.4.14):maximum0.4per cent,determined on 1.0g.ASSAYDissolve0.200g in100.0mL of water R.Dilute10.0mL of this solution to100.0mL with water R.Dilute10.0mL to 100.0mL with water R.Measure the absorbance(2.2.25)at the absorption maximum at350nm.Calculate the percentage content of C33H42O19taking thespecific absorbance to be250.STORAGEIn an airtight container,protected from light.01/2011:0694TRYPSINTrypsinum[9002-07-7]DEFINITIONTrypsin is a proteolytic enzyme obtained by the activationof trypsinogen extracted from the pancreas of mammals.It has an activity of not less than0.5microkatal per milligram, calculated with reference to the dried substance.In solution,it has maximum enzymic activity at pH8;the activity is reversibly inhibited at pH3,the pH at which it is most stable. PRODUCTIONThe animals from which trypsin is derived must fulfil the requirements for the health of animals suitable for human consumption.The method of manufacture is validated to demonstrate that the product,if tested,would comply with the following test. Histamine(2.6.10):not more than1μg of histamine base per 0.2microkatal of trypsin e a10g/L solution of the substance to be examined in0.0015M borate buffer solution pH8.0R inactivated by heating on a water-bath for30min. Carry out dilutions with a9g/L solution of sodium chloride R. CHARACTERSAppearance:white or almost white,crystalline or amorphous powder,hygroscopic if amorphous.Solubility:sparingly soluble in water.IDENTIFICATIONA.Dilute1mL of solution S(see Tests)to100mL withwater R.In a depression in a white spot-plate,mix0.1mL of this solution with0.2mL of tosylarginine methyl ester hydrochloride solution R.A reddish-violet colour develops within3min.B.Dilute0.5mL of solution S to5mL with water R.Add0.1mL of a20g/L solution of tosyl-lysyl-chloromethanehydrochloride R.Adjust to pH7.0,shake for2h and dilute to50mL with water R.In one of the depressions of awhite spot-plate,mix0.1mL of this solution with0.2mL of tosylarginine methyl ester hydrochloride solution R.Noreddish-violet colour develops within3min.TESTSSolution S.Dissolve0.10g in carbon dioxide-free water R and dilute to10.0mL with the same solvent.Appearance of solution.Solution S is not more opalescent than reference suspension III(2.2.1).pH(2.2.3):3.0to6.0for solution S.Specific absorbance(2.2.25):13.5to16.5,determined at the absorption maximum at280nm;maximum7.0,determined at the absorption minimum at250nm.Dissolve30.0mg in0.001M hydrochloric acid and dilute to 100.0mL with the same acid.Chymotrypsin.Test solution.To1.8mL of buffer solution pH8.0R add7.4mL of water R and0.5mL of0.2M acetyltyrosine ethyl ester R. While shaking the solution,add0.3mL of solution S and start a timer.After exactly5min,measure the pH(2.2.3). Reference solution.Prepare in the same manner as the test solution,replacing solution S by0.3mL of a0.5g/L solution of chymotrypsin BRP,and measure the pH(2.2.3)exactly5min after adding the chymotrypsin.The pH of the test solution is higher than that of the reference solution.Loss on drying(2.2.32):not more than5.0per cent,determined on0.500g by drying at60°C at a pressure not exceeding0.67kPa for2h.Microbial contaminationTAMC:acceptance criterion104CFU/g(2.6.12).TYMC:acceptance criterion102CFU/g(2.6.12).3156See the information section on general monographs(cover pages)EUROPEAN PHARMACOPOEIA 7.0Tryptophan Absence of Escherichia coli (2.6.13).Absence of Salmonella (2.6.13).ASSAY The activity of trypsin is determined by comparing the rate at which it hydrolyses benzoylarginine ethyl ester hydrochloride R with the rate at which trypsin BRP hydrolysesthe same substrate in the same conditions.Apparatus .Use a reaction vessel of about 30mL capacityprovided with:—a device that will maintain a temperature of 25.0±0.1°C;—a stirring device (for example,a magnetic stirrer);—a lidwith holes forthe insertion of electrodes,the tip ofa burette,a tube for the admission of nitrogen and the introduction of reagents.An automatic or manual titration device may be used.For the latter,the burette is graduated in 0.005mL and the pHmeter is provided with a wide-range scale and glass-calomel or glass-silver-silver chloride electrodes.Test solution .Dissolve sufficient of the substance to beexamined in 0.001M hydrochloric acid and dilute to 25.0mLwith the same acid in order to obtain a solution containingapproximately 700nanokatals per millilitre.Reference solution .Dissolve 25.0mg of trypsin BRP in 0.001M hydrochloric acid and dilute to 25.0mL with the same acid.Store the solutions at 0-5°C.Warm 1mL of each solution to about 25°C over 15min and use 50μL of each solution for each titration.Carry out the titration in an atmosphere ofnitrogen.Transfer 10.0mL of 0.0015M borate buffer solution pH 8.0R to the reaction vessel and,while stirring,add 1.0mL of a freshly prepared 6.86g/L solution of benzoylarginine ethyl ester hydrochloride R .When the temperature is steady at 25.0±0.1°C (after about 5min)adjust to pH 8.0exactly with 0.1M sodium hydroxide .Add 50μL of the test solution and start a timer.Maintain at pH 8.0by the addition of 0.1M sodium hydroxide,thetip of the microburettebeing immersed in the solution;note the volume added every 30s.Follow thereaction for 8min.Calculate the volume of 0.1M sodium hydroxide usedpersecond.Carry outa titration in the same manner using the reference solution and calculate the volume of 0.1M sodium hydroxide used per second.Calculate the activity in microkatals per milligram using the following expression:m =mass of the substance to be examined,in milligrams;m ′=mass of trypsin BRP ,in milligrams;V =volume of 0.1M sodium hydroxide used per second by the test solution;V ′=volume of 0.1M sodium hydroxide used per second by the reference solution;A =activity of trypsin BRP ,in microkatals per milligram.STORAGE In an airtight container,protected from light,at a temperature of 2°C to 8°BELLING The label states:—the activity in microkatals per milligram;—for the amorphous substance,that it is hygroscopic.01/2009:1272corrected 7.0TRYPTOPHANTryptophanumC11H 12N 2O 2M r 204.2[73-22-3]DEFINITION(S )-2-Amino-3-(1H -indol-3-yl)propanoic acid.Content :98.5per cent to 101.0per cent (dried substance).CHARACTERSAppearance :white or almost white,crystalline or amorphous powder.Solubility :sparinglysoluble in water,slightly soluble in ethanol(96per cent).It dissolves in dilute solutions of mineral acids and alkali hydroxides.IDENTIFICATIONFirst identification:A,B.Second identification:A,C,D.A.Specific optical rotation (see Tests).B.Infrared absorption spectrophotometry (2.2.24).Preparation :discs.Comparison :tryptophan CRS .C.Examine the chromatogramsobtained in the test for ninhydrin-positive substances.Results:the principal spot in the chromatogram obtained with test solution (b)is similar in position,colour and sizeto the principalspot in the chromatogram obtained withreference solution (a).D.Dissolve about 20mg in 10mL of water R .Add 5mL of dimethylaminobenzaldehyde solution R6and 2mL ofhydrochloric acid R1.Heat on a water-bath.A purple-bluecolour develops.TESTSAppearance of solution .The solution is clear (2.2.1)and notmore intensely coloured than reference solution BY 6(2.2.2,Method II ).Dissolve 0.1g in 1M hydrochloric acid and dilute to 10mL with the same acid.Specific optical rotation (2.2.7):−30.0to −33.0(dried substance).Dissolve 0.25g in water R ,heating on a water-bath if necessary,and dilute to 25.0mL with the same solvent.Ninhydrin-positive substances .Thin-layerchromatography(2.2.27).Solvent mixture :glacial acetic acid R ,water R (50:50V/V ).Test solution(a).Dissolve 0.10g of the substance to be examined in the solvent mixture and dilute to 10mL with thesolventmixture.Test solution (b).Dilute 1mL of test solution (a)to 50mL with the solvent mixture.Referencesolution (a).Dissolve 10mg of tryptophan CRS in the solvent mixture and dilute to 50mL with the solvent mixture.Reference solution (b).Dilute 5mL of test solution (b)to 20mL with the solvent mixture.General Notices (1)apply to all monographs and other texts 3157。
欧洲药典EP6.0-2.6.12微生物限度
2.6.12非无菌产品的微生物限度检查（总的需氧菌菌落计数）本章包括两种检验方法。
第一种方法给出的是测定适用性的参考方法。
因些在一个专论中依照本法就意味着依从第一种方法，除非特别指出要使用第二种方法。
第二种方法也是欧洲药典的官方组成部分，并且值得注意的是第二种方法特别适用于销售认可。
一旦该相关专论被修订就意味着将用第二种方法替代第一种方法。
第二种方法包含日本药典和美国药典的共同部分使其能够协调。
A．欧洲药典方法该试验方法所讲的是在需氧条件下生长的嗜温性细菌和真菌类微生物的定量检测。
设计该试验的最初目的是以审疑的态度为了测定一种物质按照欧洲药典的检测方法是否符合微生物的特定限定要求。
如果是以这种目的来测定的话，根据下述方法，包括所需的样品数和按照下面方法来解释结果。
该法也用来测定药典所描述的抗菌保留的有效性（5.1.3）。
此外，该法也可以用来监测原料质量同时也可以用来作为微生物质量检测的指导方针（5.1.4）。
如果是用来指导以下目的，如生产厂家的原料检测和/或终产品的检测或终点判定，则包括所需样品数和结果解释的试验方法就必须在生产厂家和主管当局之间达成一致。
执行该方法所设计的实验条件就必须避免所测产品受到意外污染。
避免污染所采取的措施不侧够影响任何所测的微生物。
如果所测产品有抗菌活性，则该产品活性必须补充分中和掉。
如果因为该种目的使用灭活剂则必须证明该灭活剂对微生物的有效性和无毒性。
测定总的需氧微生物数通过微孔滤膜法或专论中所描述的平板菌落计数法。
当没有其它方法可以釆用来测定细菌数时保留最大可能数（Most Probable Number, MPN）.选择哪种应该根据产品的特性和可预计的微生物数等因素来选择。
任何选择的方法必须通过合理的验证。
当根据5.1.3或5.1.4使用时，可以使用平板浇注法和表面扩散法，和微孔滤膜法。
样品制备：抽样检验方法：所选样品必须遵循抽样样品规则。
抽样检验的结果依赖于下列因素：如样品批号，不可接受的高污染产品的健康危害，产品特性，可预料的污染程度等。
欧洲药典质量标准的起草技术指南,英文版
European Directorate for the Quality of Medicines & HealthCare6© Council of Europe, 67075 Strasbourg Cedex, France - 2011All rights reservedMaking copies of this fi le for commercial purposes or posting this fi le on a web site that is open to public consultation is strictly prohibited.TECHNICAL GUIDE FOR THE ELABORATION OF MONOGRAPHS6th Edition – 2011CONTENTS1.INTRODUCTION (6)1.1.P URPOSE OF THE G UIDE (6)1.2.T EST PROCEDURES (6)1.3.E QUIPMENT (7)1.4.Q UANTITIES (7)1.5.R EAGENTS (9)1.6.C OMMERCIAL NAMES (9)1.7.R EFERENCE STANDARDS (10)2.MONOGRAPH ON A SUBSTANCE FOR PHARMACEUTICAL USE (10)2.1.D EFINITION (11)binations (12)2.1.2.Content (12)2.2.C HARACTERS (14)2.2.1.Appearance (14)2.2.2.Taste (15)2.2.3.Odour (15)2.2.4.Solubility (15)2.2.5.Stability factors (15)2.2.6.Hygroscopicity (15)2.2.7.Solid-state properties (16)2.2.8.Other characteristics (16)2.2.9.Behaviour in solution (16)2.3.I DENTIFICATION (17)2.3.1.General (17)2.3.1.1.Methods requiring complex instrumentation (18)2.3.1.2.Other methods (18)2.3.2.Infrared absorption spectrophotometry (18)2.3.2.1.Salts of organic acids or bases (18)2.3.2.2.Chemically related substances (18)2.3.2.3.Polymorphism (19)2.3.2.4.Optical isomers (19)2.3.3.Ultraviolet and visible absorption spectrophotometry (19)2.3.4.Melting point, freezing point and boiling point (20)2.3.5.Specific optical rotation (21)2.3.6.Thin-layer chromatography (21)2.3.7.Gas chromatography and liquid chromatography (21)2.3.8.Chemical reactions (22)2.4.T ESTS (22)2.4.1.General (22)2.4.2.Titles (22)2.4.3.Solution S (23)2.4.4.Appearance of solution (24)2.4.4.1.Clarity and degree of opalescence (24)2.4.4.2.Degree of coloration (25)2.4.5.pH and Acidity or alkalinity (25)2.4.6.Optical rotation (27)2.4.7.Absorption spectrophotometry (ultraviolet and visible) (27)2.4.8.Related substances (28)2.4.8.1.Thin-layer chromatography (TLC) (32)2.4.8.2.Liquid chromatography (LC) (33)2.4.8.3.Gas-liquid chromatography (GC) (37)2.4.8.4.Capillary electrophoresis (CE) (38)2.4.9.Readily carbonisable substances (39)2.4.10.Foreign anions and/or cations (39)2.4.11.Heavy metals (40)2.4.12.Loss on drying (41)2.4.13.Thermogravimetry (2.2.34) (42)2.4.14.Semi-micro determination of water (Karl Fischer – 2.5.12) (42)2.4.15.Micro determination of water (2.5.32) (42)2.4.16.Gas chromatographic determination of water (43)2.4.17.Determination of water by distillation (2.2.13) (43)2.4.18.Sulfated ash (2.4.14) (43)2.4.19.Residue on evaporation (43)2.4.20.Residual solvents (43)2.5.A SSAY (44)2.5.1.Ultraviolet and visible spectrophotometry (44)2.5.1.1.Direct measurement (44)2.5.1.2.Measurement after a colour reaction (45)2.5.2.Volumetric analysis (45)2.5.3.Chromatography (46)2.5.4.Determination of nitrogen by sulfuric acid digestion (semi-micro method) (46)2.6.S TORAGE (46)2.7.L ABELLING (47)2.8.I MPURITIES (47)2.9.F UNCTIONALITY-RELATED CHARACTERISTICS (47)3.ANALYTICAL VALIDATION (48)3.1.D EFINITIONS AND TERMINOLOGY (48)3.1.1.Introduction (48)3.1.2.Types of analytical procedures to be validated (48)3.1.3.Validation characteristics and requirements (49)3.1.4.Glossary (50)3.2.M ETHODOLOGY (52)3.2.1.Introduction (52)3.2.2.Specificity (53)3.2.2.1.Identification (53)3.2.2.2.Assays and impurity tests (53)3.2.3.Linearity (54)3.2.4.Range (54)3.2.5.Accuracy (55)3.2.5.1.Assay (55)3.2.5.2.Impurities (quantification) (56)3.2.5.3.Recommended data (56)3.2.6.Precision (56)3.2.6.1.Repeatability (56)3.2.6.2.Intermediate precision (56)3.2.6.3.Reproducibility (56)3.2.6.4.Recommended data (57)3.2.7.Detection limit (57)3.2.7.1.Based on visual evaluation (57)3.2.7.2.Based on signal-to-noise ratio (57)3.2.7.3.Based on the standard deviation of the response and the slope (57)3.2.7.4.Recommended data (58)3.2.8.Quantitation limit (58)3.2.8.1.Based on visual evaluation (58)3.2.8.2.Based on signal-to-noise ratio (58)3.2.8.3.Based on the standard deviation of the response and the slope (58)3.2.8.4.Recommended data (59)3.2.9.Robustness (59)3.2.10.System suitability testing (59)3.3.S PECIFIC APPLICATION TO M ETHODS USED IN THE P HARMACOPOEIA (60)3.3.1.Optical rotation (2.2.7) (60)3.3.1.1.Introduction (60)3.3.1.2.Identification (60)3.3.1.3.Tests (60)3.3.1.4.Assay (61)3.3.2.Ultraviolet spectrophotometry (2.2.25) (61)3.3.2.1.Identification (61)3.3.2.2.Limit test (61)3.3.2.3.Assay (61)3.3.3.Non-instrumental limit tests (61)3.3.3.1.Appearance of solution (2.2.1 and 2.2.2) (61)3.3.3.2.Acidity or alkalinity (62)3.3.3.3.Limit tests for anions/cations (2.4) (62)3.3.4.Atomic absorption spectrometry (2.2.23) (63)3.3.4.1.Specificity (63)3.3.4.2.Calibration (63)3.3.4.3.Matrix effects (64)3.3.4.4.Detection and quantification limit (based on the standard deviation of the blank) (64)3.3.5.Separation techniques (65)3.3.5.1.Thin-layer chromatography (2.2.27) (65)3.3.5.2.Liquid chromatography (2.2.29) (66)3.3.5.3.Gas chromatography (2.2.28) (67)3.3.6.Semi-micro determination of water (2.5.12) (69)3.3.7.Volumetric titrations (2.5.11; 2.2.19; 2.2.20) (69)3.3.8.Peptide identification by nuclear magnetic resonance spectrometry (2.2.64) (72)TECHNICAL GUIDE FOR THE ELABORATIONOF MONOGRAPHS1.INTRODUCTION1.1.P URPOSE OF THE G UIDEThis document is a guidance for the authors of monographs and also a means of communicating to the users of the European Pharmacopoeia, especially industry, licensing authorities and official medicines control laboratories, the principles for the elaboration of monographs. Since the principles applied and guidance given for the elaboration of monographs should be the same as those applied by licensing authorities, the Technical Guide may also serve as a guideline in the elaboration of specifications intended for inclusion in licensing applications.It is necessary to bear in mind that a monograph will be a mandatory standard and must be applicable in licensing procedures in all Member States of the Convention on the Elaboration of a European Pharmacopoeia. The procedures for the tests and assays in the individual monographs must therefore have been validated according to the current practice at the time of their elaboration.1.2.T EST PROCEDURESThe methods chosen for the identification tests, purity tests and assay(s) constituting the bulk of a pharmacopoeial monograph are preferably those already described and utilised in the European Pharmacopoeia. In this context, the author of a monograph is referred not only to the General Methods of the Ph. Eur. but also to published monographs on similar materials. The above considerations aim at ensuring a reasonable degree of harmonisation within the Pharmacopoeia and they only apply in cases where the methods are found to be adequate for the specific purposes. However, due attention is also to be paid to the development of new methods that offer significant improvements in terms of sensitivity, precision, accuracy or discriminating power (selectivity).Methods included in monographs must be validated as described in the section on analytical validation and other relevant specific sections of this guide. Validation reports are provided to the EDQM but are not published or otherwise provided to users.The test procedures included in a monograph should be verified in 2 or more laboratories and the laboratory reports on this verification should be provided to the EDQM to ensure future traceability.The instructions describing any method of analysis cover all factors that can influence the results and that are deemed essential to enable an experienced analyst working according to acknowledged laboratory practices, yet without necessarily having any prior knowledge of the investigation in question, to perform the analysis. Variations in the description of similar methods are to be avoided.If an analytical procedure is, or may be, expected to be used generally or if it requires a lengthy description and is used more than once, it may be proposed for inclusion in the general chapters of the Pharmacopoeia, to be referred to in the individual monographs. The methods are prescribed on the scale conventionally applied in the Pharmacopoeia except in cases where for reasons of availability of the material to be analysed, or because of its toxicity or its cost, work on a small scale would be advantageous.1.3.E QUIPMENTIf the equipment utilised for a method of analysis is not generally available in the States party to the European Pharmacopoeia Convention, it must be possible to have it constructed according to its description in the Pharmacopoeia.1.4.Q UANTITIESIn prescribing the quantities, i.e. masses and volumes, of substances, reagents, and solvents to be taken for identifications, tests and assays, it is the practice of the Pharmacopoeia to indicate in detail the precision with which they are to be measured (see General Notices). It is therefore necessary to take this aspect into consideration when drafting Pharmacopoeial texts.As guidance to minimise errors in the preparation of analytical solutions, Table 1, giving estimations of the relative uncertainty, is to be consulted.In order to avoid either the use of extremely low amounts or an unnecessarily large expenditure of solvents, a dilution series will often have to be prescribed for the preparation of dilute solutions used particularly for spectrophotometric measurement. In this context not all combinations of (usually 2 or 3) dilution steps will contribute equally to the random error of the dilution procedure. If critical for the purpose, the optimal dilution is prescribed in consideration of the relative errors (capacity tolerance divided by nominal volume) associated with the various sizes of volumetric pipettes and volumetric flasks commonly used for these operations (taking the usual formula: square root of the sum of the squares of individual relative errors, to estimate the relative dilution error).Tables giving the optimal number and nature of dilution steps needed to achieve a given dilution ratio, based upon given specifications for the capacity tolerances of volumetric glassware, are available in the literature. For guidance see Table 2 (it is to be noted that these factors do not include reading errors).Table 1 – Relative uncertainties in the preparation of analytical solutionsAn uncertainty of 0.2 mg for the weighing procedure has been assumed for the calculations of the percentage relative uncertainties.Table 2 –Relative errors for dilution with analytical glassware (pipettes P/flasks F)Adapted from R.B. Lam and T.L. Isenhour, Minimizing relative error in preparation of standard solutions by judicious choice of volumetric glassware, Analytical Chemistry, 1980, 53, 1158-1161.1.5.R EAGENTSWhen the quality of a reagent substance in one or more respects is critical for its intended use, it must be carefully defined, when necessary by prescribing appropriate tests to demonstrate its suitability. Normally, analytical grade reagents are employed in which case it is sufficient to give the name of the reagent, the CAS number and its formula.Whenever possible, the reagent substances, reagent solutions, volumetric solutions and standard solutions for limit tests already described the Reagents chapter of the European Pharmacopoeia are to be employed. Simple solutions of reagent substances or solutions that are prepared for use on a single occasion are to be described in the monograph itself.The use of reagents that are acknowledged to be extremely toxic or otherwise hazardous (e.g. carcinogenic), is to be avoided, especially in circumstances where their dangerous properties are difficult to control, e.g. when handled as fine powders or in spray reagents. The use of a number of substances that are prohibited or restricted in one or more of the States party to the European Pharmacopoeia Convention is also to be avoided.1.6.C OMMERCIAL NAMESCommercial names should be given as footnotes in draft monographs systematically for chromatography columns/plates and in other cases wherever it will be useful for analysts (test kits, reagents that are available from a single supplier, etc.). Commercial names are notincluded in the text published in the Pharmacopoeia but are transferred to the EDQM website Knowledge Database after adoption of the monograph.1.7.R EFERENCE STANDARDSThe policy and procedures regarding reference standards are described for information in general chapter 5.12. Reference standards.Procurement, establishment, storage and monitoring of reference standards are the responsibility of the EDQM. Many reference standards, notably those for control of impurities, are available only in limited quantities. Before publication of a monograph in Pharmeuropa, the required quantities of reference standards should be supplied to the EDQM, who will also advise on the best strategy for optimising the use of substances that are available in limited quantities (for example, preparation of a spiked substance rather than supply of the single substance). The aim of the EDQM is to present the reference standards for adoption at the same time as the monograph or, failing that, by the time of publication at the very latest.From the 5th Edition onwards, a change was made to the policy for establishment of an IR reference spectrum, which was previously the option of choice where the only use for a reference standard was IR identification. Preference is now given to chemical reference substances over reference spectra, except in special cases, for example where provision of a reference substance entails practical difficulties.Many reference standards are available in limited quantities, notably impurities, and the amount prescribed for preparation of solutions must be kept to a minimum.2.MONOGRAPH ON A SUBSTANCE FORPHARMACEUTICAL USEMonographs are based on the specifications for substances used in medicinal products approved in Member States. When a monograph is added to the work programme, enquiries are made by the EDQM to identify manufacturers of such substances and all data received is taken into account for preparation of the monograph. Interested parties should be invited to participate in the elaboration of the monograph before publication in Pharmeuropa, since the 3-month public period will often be too short for all interested parties to check the draft monograph.Prior to the preparation of any monograph, it is essential to gather as much information as possible on the substance in question.In particular it is necessary to ascertain:∙whether the substance is of natural, synthetic or semi-synthetic origin;∙whether the substance is a mixture or a single entity;∙the method(s) of preparation in detail;∙whether there are different crystalline forms, since the properties of the substance may vary in accordance with this parameter;∙whether both an enantiomer as well as the racemate or other mixtures of enantiomers are available;∙whether different hydrates are available;∙whether different entities (acid, base, salt, etc) are available.The Pharmacopoeia and other relevant documents on the state of work must be consulted to see if monographs on similar substances exist or are being elaborated. If monographs or drafts on similar substances already exist, it is important to ensure that the monograph to be elaborated follows the same approach unless there are good reasons to deviate, e.g. developments in analytical techniques.Substances that are to be described in a monograph may be members of a group of very similar substances (family). This holds true especially for excipients such as macrogols. A master monograph is to be drafted clearly stating the attributes common to all members of the family and that can be used to identify single members of the family (family monograph).All active substances and excipients described in the European Pharmacopoeia are subject to the provisions of the general monograph Substances for pharmaceutical use (2034).Title. The International Nonproprietary Name (INN) established by the World Health Organization should be used wherever it is available; it is supplemented as appropriate by the name of the anion or cation and by “hydrate”, “dihydrate”, “hydrated” (for ill-defined degrees of hydration) or “anhydrous” (where a hydrated form is also known to exist). Formerly, the degree of hydration was not indicated in titles unless 2 forms were known to be available; existing titles of this type are not changed on revision unless it is known that 2 forms are available or if there is a public health imperative (for example, high water content that could lead to errors in formulation). Anions and cations are indicated as “mono-”, “di-”, “tri-”, etc., as appropriate.Where a substance is used in approved medicinal products for veterinary use only in Member States, “for veterinary use” is included in the title.2.1.D EFINITIONThe chemical structure must be ascertained with the greatest possible precision in order to establish the exact:∙graphic formula;∙empirical formula and relative molecular mass. The latter is calculated as follows: first, the relative atomic masses, or multiples thereof, are added together using all the figures of the International Table of Relative Atomic Masses; the total is then rounded off to 4 significant figures if the initial digit is 1,2,3,4 or 5, or to 3 significant figures if the initial digit is 6,7,8 or 9; the last figure is increased by 1 when the part rejected exceeds 1 half-unit. When the part rejected is equal to or less than 1 half-unit, the last figure taken is not modified;∙chemical name. This implies investigating in particular:o the possible existence of isomers so as to be able to specify which isomer is used or, otherwise, to state that the product is a mixture of isomers;o in the case of an optical isomer, it is insufficient to take into account only the direction of the optical rotation. The absolute configuration is given by the R/Ssystem at the asymmetrical centre(s) or any other appropriate system (e.g., forcarbohydrates and amino acids);o ascertaining the state of hydration or solvation so as to distinguish clearly between the well-defined hydrates and solvates and the products that containvariable quantities of solvent(s). As regards the former, water or solventcontent ranges are specified but for the latter only a maximum content is given.When a substance exists both in a water-free or solvent-free form and in theform of (a) hydrate(s) or (a) solvate(s) with different water or solvent contents,and if all these forms are used, they are normally treated as individualsubstances requiring separate monographs.Some chemical substances, particularly those obtained from raw materials of natural origin and substances produced by fermentation, may not be easily separated from certain related substances (for instance, quinine salts). These may be treated as:∙ a chemical product when obtained in a very pure state and when they can be assayed by a physico-chemical method;∙ a substance accompanied by a certain proportion of related substances, giving an exact definition of the main component only (e.g. neomycin);∙ a mixture of several components, sometimes difficult to define, where an overall description may suffice (e.g. nystatin).Where applicable, the origin of the substance must be specified (name and strain of the organism from which the substance is derived). Where applicable, the monograph indicates that the substance is semi-synthetic and derived from a fermentation product [to clarify application of the general monograph Substances for pharmaceutical use (2034)].binationsIn therapeutics, more or less well-defined chemical combinations (for instance, theophylline-ethylenediamine) or even mixtures are sometimes used. In such cases, it is necessary to specify precisely each component of the combination or mixture, with its chemical structure and the proportion in which it is present.2.1.2.ContentThe substance described by a monograph is never a wholly pure substance but contains a limited proportion of impurities. The content is therefore an important part of the definition. Assay limits are specified between which the content must fall. The assay limits must take account of the precision of the method as well as the acceptable purity of the substance. Assay limits are normally expressed with reference to the dried or anhydrous substance; correction for residual solvent is understood [see Substances for pharmaceutical use (2034)].For a non-specific assay (for example, titrimetry) the assay limits are usually 99.0-101.0 % (unless otherwise justified). For a specific assay using a separation technique (for example, liquid or gas chromatography), the upper assay limit is normally 102.0 %; the lower assay limit will take any necessary account of the impurities present and may therefore be lower than 98.0 %.In setting these limits for the active ingredient content, account is taken of: ∙the method of preparation, which determines the degree of purity that may be reasonably required;∙the reproducibility and accuracy of the analytical method;∙where a separation technique is employed both for the test for related substances and the assay, content limits are set taking into account the maximum permitted amount of impurities and the analytical error;∙the evaluation of the tolerable degree of deterioration during storage;∙ a sufficient number of experimental results obtained on several batches (at least 3), if possible, of different origins and ages.When the substance to be examined contains only impurities that do not interfere with the assay, or when it contains only a very low proportion of impurities interfering with the assay, the results of the assay can be used directly. It will then be stated that: “the substance contains not less than x % and not more than the equivalent of y % (at least 100.5 %, but often a little more) of [chemical definition of the pure product]”. The content of the substance is usually expressed with reference to the anhydrous or dried substance. In certain cases, it is necessary to express the content on a solvent-free basis or a solvent-free and anhydrous basis. The general monograph Substances for pharmaceutical use (2034) has a provision for calculation of content with reference to the solvent-free substance, which covers cases where the test for residual solvent is not included in a specific monograph.In cases where the water content is high (e.g. in the case of disodium phosphate dodecahydrate), limits of content may be expressed with reference to the hydrated substance, taking into account the molecular mass of the hydrated form (only for well-defined and stable hydrates) or with reference to the s ubstance “as is” in combination with determination of water content/loss on drying.When the substance to be examined contains a relatively large proportion (a few %) of impurities, which are determined at the same time as the active ingredient, an appropriate wording is to be used (for instance, in the case of quinine salts: “x % of total alkaloid salts, expressed as quinine salts”).Exceptionally reference is made to only a part of the molecule or to an element (for example, assay of magnesium oxide in light magnesium carbonate or assay of magnesium in magnesium stearate).In the case of antibiotics determined by microbiological assays, the active ingredient content is expressed in International Units, where these exist, and only a minimum value is given. See also section 2.5. Assay.2.2.C HARACTERSAs defined in the General Notices, statements under the heading CHARACTERS are not to be interpreted in a strict sense and are not regarded as analytical requirements.The principal items that may be referred to under this heading are the following.2.2.1.AppearanceThis description will normally embrace colour and physical form. The term “white” is not used without qualification since, if viewed against a standard white material, very few pharmaceutical materials will appear truly white. It is, of course, not intended that such a comparison be made but experience shows that certain users of the Pharmacopoeia may insist on doing so as part of a purchasing contract. The term “white or almost white” is used instead. Where positive colours are to be described, this is done in terms of primary colours or combinations of primary colours.Colour: the following descriptive terms are used:black orangeblue pinkbrown redcolourless violetgreen white/almost whitegrey yellowCompound terms may be used:English Frenchgreenish-blue bleu-vertbluish-green vert-bleuviolet-red rouge-violetreddish-violet violet-rougebrownish-red rouge-brunreddish-brown brun-rougeIn English, the dominant is placed second, whereas in French, it is placed first. Expressions such as lemon-yellow, buff, salmon-pink are to be avoided; standard dictionaries give equivalents for such terms as spectral colours with suitable qualifiers (for example, buff is described as “dull yellow”). The following adjectives are also used; light, slight, fluorescent, intense, pale, dull, deep, dark.It is to be noted that the allowed colours and colour combinations also apply to the description of the colour changes of indicators when used in acid/alkalinity tests or in titrimetric assay procedures.2.2.2.TasteThe taste is not to be taken into consideration.2.2.3.OdourIn general, no reference is made to odour. In particular no reference to odour is made for those materials that would constitute a hazard if inhaled. Mention of odour in other cases must be justified.2.2.4.SolubilityA method recommended for the estimation of solubility is given in general chapter5.11. Characters section in monographs. All solubilities are quoted in the general terms defined in the General Notices. Solvents quoted are normally confined to water, an alcohol and a lipophilic solvent. Solubilities in chloroform and ether are not mentioned. In special cases the solubility of different samples of a material may vary rather considerably even though their composition is still within the limits set by the monograph. The solubilities in the solvents thereby affected are then given to cover more than one solubility class, e.g. “spar ingly soluble to soluble in...”. The solubilities or miscibilities in other solvents with which the material is often combined in practice such as fatty oils, etc., may also be mentioned. In some cases it may be useful to specify solubility in alkalis or acids and, particularly in cases of materials that are very insoluble in the above-mentioned solvents, a special solvent may be indicated, e.g. dimethylformamide or dimethyl sulfoxide. It is not necessary to specify the solubility in every solvent that is used in performing the tests of the monograph itself.2.2.5.Stability factorsEvidence of instability due to exposure to air, light and for moisture is to be given, e.g. physostigmine sulfate turns red when exposed to air and light. Any such statement under CHARACTERS is given separately from the description of a pharmacopoeial material.2.2.6.HygroscopicityA pragmatic method recommended for the determination of the tendency of a substance to take up atmospheric water (rather than a true determination of hygroscopicity) is given in general chapter 5.11. Characters section in monographs. Some substances are hygroscopic or deliquescent, which results in difficulties for the analyst during weighing procedures. In such cases, this is indicated using the terminology defined in general chapter 5.11. Characters section in monographs for information of the analyst as an alert for precautions to be taken in handling the substance.。