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实训药物溶解度测定5关键字溶解度;中国药典;美国药典;欧洲药典;日本药典溶解度是一种物理性质,是药物的重要参数之一药物研发过程中,药物的溶解度在药物制剂的设计、制备、质量控制中具有重要的意义,也是直接影响药物体内吸收与生物利用度的重要因素,尤其对新药而言更有意义在质量研究过程中必须考虑药物的溶解度,这关系到溶液的制备、流动相的选择等分析的小伙伴对溶解度测定应该是很熟悉的,大家有没有为溶解度的测定方法纠结过?在什么样的环境中操作?怎么配制样品?使用什么容器?多少溶剂溶解多少样品?振摇几次?振摇多久?今天,小编详细介绍各国药典(中国药典、欧洲药典、美国药典、日本药典)中溶解度的测定方法,博采各家之长,解决以上疑惑,让咱们从今以后能够顺顺利利地测定药物的溶解度中国药典1中国药典对溶解度划分为七个类别,并且七个类别都是独立操作,这与欧洲药典不同2溶解度是药品的一种物理性质各品种项下选用的部分溶剂及其在该溶剂中的溶解性能,可供精制或制备溶液时参考,对在特定溶剂中的溶解性能需作质量控制时,在该品种〔检查〕项F作具体规定.药品的近似溶解度以下列名词术语表示极易溶解系指溶质lgml能在溶剂不到1ml中溶解;易溶系指溶质lgml能在溶剂1〜不到10ml中溶解;溶解系指溶质能在溶剂10〜不到30ml中溶解;系指溶质1晨ml能在溶剂30〜不到100ml中溶解系指溶质lgmD略溶能在溶剂100〜不到lOOOrnl中溶解;系指溶质lgml能在溶剂1000〜不到10000ml中溶解;系指溶质lgml微溶极微溶在溶剂10000ml中不能完全溶解解试验法除另有规定外,称取研成细粉的供试品或hi取液体供试品,胃于25七±2七一定容量的溶剂中,几乎不溶或不溶每隔5分钟强力振摇30秒钟观察30分钟内的溶解情况,如无目视可见的溶质颗粒或液滴时,即视为完全溶解.3物理常数包括相对密度、憎程、熔点、凝点、比旋度、折光率、粘度、吸收系数、碘值、里化值和限值等,其测定结果不仅对药品具有鉴别意义,也可反映药品的纯度,是评价药品质量的主要指标之一.具体操作过程需要换算为可行的称样量、溶剂量不能全部简单地直接取的样品量!1go药典位置四部凡例项目与要求极易溶解溶质能在不到中溶解;1g ml1ml易溶溶质能在溶剂•不到中溶解1g ml110ml溶解溶质能在溶剂不到中溶解1g ml10-30ml溶解度划分七略溶溶质能在溶剂.不到中溶解1g ml30100ml个微溶溶质〈能/列不到中溶解1g ml100-1000ml极微溶解溶质能在溶剂不到中溶解1g ml1000-10000ml几乎不溶或不溶溶质在溶剂中不能完全溶解1g ml10000ml除另有规定外,称取研成细粉的供试品或量取液体供试品,于©士252试验方法;一定溶剂中,每隔分钟强力振摇秒观察分钟内的溶解情况,53030如无目视可见的溶质颗粒或.即视为完全溶解°细粉是指全部通过五号筛目,筛孔内径微米微米,并含能80180±
7.6注意事项通过六号筛不少于的粉末95%头狗睡酚钠举例【性状】本品为白色或类白色的结晶性粉末几乎无臭本品在水中易溶,在乙醇中微溶,在乙醛中不溶c美国药典2美国药典将溶解度也划分为七个类别,与中国药典一致,但是十分简略,没有具体的操作过程药典位置
5.30Description andSolubility溶解度划分七个一份溶质所需要的溶剂量极易溶解Very soluble1易溶Freely soluble包括1-101溶解Soluble包括10-3010略溶Sparingly soluble包括30-10030微溶Slightly soluble包括100-1000100极微溶解Very slightly soluble包括1000-10000100010000几乎不溶或不溶Practically insoluble,or Insoluble举例Sodium HydrosulfiteWhiteor grayish-white crystalline powder.Soluble in water:slightly soluble in alcohol.Gradually oxidizesin air,more readilywhen insolution,to bisulfite,acquiring anacid reaction.Is affectedby light.ingredients1comply withapplicable regulatoryrequirements,Conformance.and2do notinterfere withthe assaysand testsprescribed forTheair in a containerof anofficial articlemay,wheredetermining compliancewith compendialstandards.appropriate,be evacuatedor bereplaced bycarbon dioxide,
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30.Description andSolubilityhelium,argon,or nitrogen,or bya mixtureof thesegases.The useOnlywhere aquantitative solubilitytest isgiven in a monographofsuch gasneed notbe declaredin thelabeling.and isdesignated assuch isit atest forpurity.
5.
20.
10.Added Substancesin OfficialSubstancesA monographmay includeinformation regardingthe articlesOfficialsubstances maycontain onlythe specificaddeddescription.Information aboutan articles~*description andsubstancesthat arepermitted bythe individualmonograph.Suchsolubility alsois providedin the reference tableDescription andaddedsubstances shallnot exceedthe quantityrequired forRelativeSolubility ofUSP andNF Articles.The referencetableproviding theirintended effect.Where suchaddition ispermitted,merely denotesthe propertiesof articlesthat complywiththe labelshall indicatethe namesand amountsof anyaddedmonograph standards.The referencetable isintended primarilysubstances.for thosewho use,prepare,and dispensedrugs and/or related
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20.
20.Added SubstancesExcipients andIngredients inarticles.Although theinformation providedin monographsand theOfficialProductsinformation inthereferencetable mayindirectly assistin theSuitablesubstances andexcipients suchas antimicrobialpreliminaryevaluation of an article,it is not intendedto serveas aagents,pharmaceutical bases,carriers,coatings,flavors,standard ortest forpurity.preservatives,stabilizers,and vehiclesmay beadded toanThe approximatesolubility ofa compendialsubstance isofficialproduct toenhance itsstability,usefulness,or elegance,indicated byone of the followingdescriptive terms:or tofacilitate itspreparation,unless otherwisespecified intheindividual monograph.Added substancesand excipienbemployed solelyto impartcolormay beincorporated intoofficial productsother thanthoseintended forparenteral orophthalmic use,in accordancewithPartsofSotventRequiredfor1Partoftheregulations pertainingtothe useof colorsissued bythe FDA,DescriptiveTerm Soluteprovidedsuch addedsubstances orexcipients areotherwiseVerysoluble Lejsthan1appropriate inall respects.See alsoInjections andImplantedDrugs Products1Product QualityTests Commonto FreelysolubleFrom1to10zParenteral DosaqeForms,Specific Tests,Vehicles and addedSoluble From10to30substances,Added substances.Sparinglysoluble From30to100The proportionsof the substances constitutingthe baseinointment andsupposito7products andpreparations maybeSlightlysoluble From100to1,000varied tomaintain asuitable consistencyunder differentclimaticconditions,provided thatthe concentrationsof drugsubstances VeryslightlysolubleFrom1,000to10,000are notvaried andprovided thatthe bioavailability,therapeutic Greaterthanorequalto10,000Practicallyinsoluble,orInsolubleefficacy,and safetyof thepreparation arenot impaired.欧洲药典3欧洲药典的溶解度划分为六个类别,没有“几乎solubility不溶或不溶”这个类别01/2008:51100CRYSTALLINITY1hismethodisemployed toestablishthecrystallineoramorphousnatureofa substance.Mount afew particlesof the substance tobe examinedin mineraloilon aclean glassslide.Examine undera polarisingmicroscope.
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11.CHARACTERS SECTIONIN Crystallinepartides exhibitbirefringence andextinction positionswhenthe microscopestage isrevolved.MONOGRAPHSSOLUBILITYI heGeneral Noticesindicate thatthe statementsincluded inthe Forthis testa maximum of111mg ofsubstance foreachsolventCharacterssectionarenot tobeinterpretedinastrictsense andareandamaximumof30mL ofeach solventare necessary.not requirements.For informationof users,the methodsDissolvingprocedurerecommended toauthors ofmonographs asthe basisforShake vigorouslyfor1min andplace ina constanttemperaturestatements concerninghygroscopicity;crystallinity andsolubilitydevice,maintained ata temperatureof
25.0±
0.5℃for15min.Ifare givenbelow.the substance is not completely dissolved,repeat theshaking for1min andplace thetube inthe constanttemperature devicefor15HYGROSCOPICITYmin.This methodis tobe carriedout onasubstancethat complieswith Methodthetest forloss ondrying orwater contentof themonograph.1heWeigh100mg offinely powdered substance
902.
9.12in amethodgives anindication ofthe degreeof hygroscopicityratherstoppered tube16mm ininternal diameterand160mm long,than atrue determination.add
0.1mL ofthe solvent and proceed as described underUse aglass weighing vessel50mm inexternal diameterand15Dissolving Procedure.If the substance is completely dissolved,itmm high.Weigh thevessel andstopper啊.Place theamount ofis verysoluble.substance prescribedfor thetest forloss ondrying orwater inthe If the substance is not completely dissolved,add
0.9ml.of thevesseland weighm.Place theunstoppered vesselinasolvent and proceed as described under Dissolving Procedure.If2desiccator at25℃containing asaturated solutionof ammoniumthesubstance is completely dissolved,it isfreely soluble.chloride orammonium sulfateor placeit ina climaticcabinet setIf thesubstance is notcompletely dissolved,add
2.0mL oftheat25±1℃and80±2per centrelative humidity.Allow tostand solvent and proceed as described under Dissolving Procedure.Iffor24h.Stopper theweighingvesseland weigh叫.thesubstanceis completely dissolved,it issoluble.If thesubstanceisnotcompletely dissolved,add
7.0mL oftheCalculate thepercentage increase in massusing theexpression:solventandproceedasdescribedunderDissolvingProcedure.Ifthe substanceiscompletelydissolved,it issparingly soluble.Ifthe substanceisnotcompletelydissolved,weigh10mg offinely------x100niy—叫powderedsubstance
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9.12inastopperedtube,add
10.0ml.ofthe solventandproceedasdescribedunderDissolvingI heresult isinterpreted asfollows:Procedure.If thesubstanceiscompletelydissolved,it isslightly-deliquescent:sufficient wateris absorbedto forma liquid,soluble.-very hygroscopic increase inmass isequaltoor greaterthan Ifthesubstanceisnotcompletelydissolved,weigh1mg offinely15per cent,powderedsubstance
902.
9.12inastoppered tube,add
10.0mL ofthesolventandproceedasdescribedunderDissolving-hygroscopicincreasein massis less than15per centandProcedure.Ifthesubstanceiscompletelydissolved,it isveryequal toor greaterthan2per cent,slightly soluble.-slightly hygroscopic:increaseinmassislessthan2per centandequal toor greaterthan
0.2per cent.欧洲药典操作过程是最详细并且最简便的,体现在如下几点规定了容器---具塞试管(长度内径)
1.160mm,16mm!做过溶解度实验的小伙伴们,肯定为溶解度使
2.取样量和溶剂用量不用经过换算,取样量定为用什么容器而苦恼过!这个问题在欧洲药典这里解决了Img(极微溶解)溶剂用量也是定的
3.极易溶解、易溶、溶解、略溶这四个类别只需要(极易溶解、易溶、溶解、略溶)、(微溶)、100mg10mg取样一次,实验过程都是先从极易溶解开始,循序渐进地往下一个等级考察虽然与中美日三国药典的具体操作有差异,但是结果是一致的!欧洲药典与其他三国药典对于几个溶剂用量节点、4,10ml的划分是不一致的,比如,取样品溶30ml.100ml.1000ml1g解在溶剂中,欧洲药典为易溶,中美日药典为溶解这个10ml溶剂用量的节点是要注意的药典仪
5.11characters sectionin monographs称取供试品细粉加入溶剂按“试验方法”操作,能够完全lOOmg,
0.1mL溶解,即为极易溶解、5soluble如果不能完全溶解,加入溶疝按“试验方法”操作,能够完全溶解,
0.9ml,即为易溶freely souble如果不能完全溶解,加入溶剂按“试验方法”操作,能够完全溶解,2mL溶解度划分即为溶解souble六个如果不能完全溶解,加入溶剂按“试验方法”操作,能够完全溶7mL解,即为略溶sparingly souble如果不能完全溶解,更“称取供试品细粉加入溶剂按“试验10mg,10ml,方法”操作,能够完全溶解,即为微溶如果不能完全溶slightly souble解,重新称取供试品细粉加入溶剂按“试验方法”操作,能够Img,10ml,完全溶解,即为极微溶解very slightlyMwble称取供试品细粉置于具塞试管长度内径中,90100mg,160mm,16mm试验方法加入一定量的溶剂,振摇分钟,©±环境卜保持分钟
1250.515样品不溶解的话,重复振摇分钟,该温度下保持分钟,观察结果
115、取样量不得超过每个溶剂用量不得超过111Img,30ml、欧洲药典对于药筛的规定完全不同于中国药典,溶解度测定要求的供2注意事项试品细粉指的是孔径为微米的药筛,相当于中国药典的八号筛9090150目这里是要尤其注意的地方!DACARB AZINECHARACTERS举例Appearance:white orslightly yellowish,crystalline powder.Solubility:slightlysolubleinwaterand inanhydrous ethanol,practicallyinsoluble inmethylene chloride.日本药典4日本药典把溶解度划分为七类,表述与中美药典一致,实验过程与中国药典一致,但没有对细粉的概念进行详细说明在此不赘述举例AfloqualoncDescription Afloqualoncoccurs aswhite tolight yellow,crystals orcrystallinepowder.It issolubleinacetonitrile,sparingly solublein ethanol
99.5,and practicallyinsoluble inwater.It isgradually coloredby light.Melting point:about197℃with decomposition.总结5通过以上四家药典中溶解度的详细解读,大家是不是能判断出哪个药典的溶解度部分最优质?参考标准时,是不是就能灵活运用了?我们从以下几方面,将四家药典的不同点进行比较中国药典美国药典欧洲药典日本药典溶解度类别7767供试品要求细粉(五号筛)不明确过筛(90微米孔径)不明确样品配制需要换算需要换算直接使用需要换算称取供试品细粉
(90)称取研成细粉的供试1OOmg,加入一定量的溶剂,品或量取液体供试品,振摇1分钟,25€±
0.5(3于250c±2°C一定溶剂与中国药典试验过程不明确环境下保持15分钟,样品不中,每隔5分钟强力一致溶解的话,重复振摇1分钟,振摇30秒观察30分该温度下保持15分钟,观察结钟内的溶解情况二果中美日三国药典对于溶解度的划分是一致的,欧洲药典在溶剂用量节点上稍有不同溶解度受药物的物理化学性质(例如表面积、颗粒大小、晶型)、介质的性质、以及溶解度测定参数的控制(例如温度、时间、搅拌法)等因素的影响因此,实验过程中这些参数都是要注意的欧洲药典对溶解度的具体要求是最详细的,当需要使用中美日药典时,大家可以将欧洲药典的“样品配制”直接搬来使用!但是,不知道大家有没有注意,这样用的话会有个问题,如果套用的话,上述欧洲药典部分提出的溶剂用量节点的问题怎么办?小编的建议是称样量稍小于,就能满足中美日三国的100mg要求了要是使用的是欧洲药典,称样量只要不超过都是lllmg可以的最后小编提醒大家,在参考国外标准时,一定要按照标准所使用的药典方法!。