药物稳定性实验

1150药物稳定性Theterm“stability,”withrespecttoadrugdosageform,referstothechemicalandphysicalintegrityofthedosageunitand,whenappropriate,theabilityofthedosageunittomaintainprotectionagainstmicrobiologicalcontamination.Theshelflifeofthedosageformisthetimelapsefrominitialpreparationtothespecifiedexpirationdate.Themonographspecificationsofidentity,strength,quality,andpurityapplythroughouttheshelflifeoftheproduct.Thestabilityparametersofadrugdosageformcanbeinfluencedbyenvironmentalconditionsofstorage(temperature,light,air,andhumidity),aswellasthepackagecomponents.Pharmacopeialarticlesshouldincluderequiredstorageconditionsontheirlabeling.Thesearetheconditionsunderwhichtheexpirationdateshallapply.Thestoragerequirementsspecifiedinthelabelingforthearticlemustbeobservedthroughoutthedistributionofthearticle(i.e.,beyondthetimeitleavesthemanufactureruptoandincludingitshandlingbythedispenserorsellerofthearticletotheconsumer).Althoughlabelingfortheconsumershouldindicateproperstorageconditions,itisrecognizedthatcontrolbeyondthedispenserorsellerisdifficult.Thebeyond-usedateshallbeplacedonthecontainerlabel.就药物制剂而言，术语“稳定性”是指单位剂量药物理化性质的完整程度以及在适当情况下对微生物污染的抵抗能力。制剂的有效期指从生产至失效期的期限。在有效期内，产品须符合各论中有关鉴别、效价、质量和纯度的规定。药物制剂的稳定性参数可能受到它所贮存的环境(温度、光照、空气和湿度)的影响，还受到包装材料的影响。药典收载的药物制剂的标签应标明贮存条件。在有效期内，药品应在规定的各条件下贮存。药品在分销过程中(即从药品离开生产商后直到由配药员处理或销售者卖给消费者)必须遵守标签上规定的贮存要求。尽管对于消费者来说药品标签应标明合适的贮存条件，但是药品在由配药员或销售者到达消费者手中时，对贮存环境的控制是很困难的。药品的失效期应在容器标签上注明。StabilityProtocolsStabilityofmanufactureddosageformsmustbedemonstratedbythemanufacturer,usingmethodsadequateforthepurpose.Monographassaysmaybeusedforstabilitytestingiftheyarestability-indicating(i.e.,iftheyaccuratelydifferentiatebetweentheintactdrugmoleculesandtheirdegradationproducts).Stabilityconsiderationsshouldincludenotonlythespecificcompendialrequirements,butalsochangesinphysicalappearanceoftheproductthatwouldwarnusersthattheproduct'scontinuedintegrityisquestionable.Stabilitystudiesonactivesubstancesandpackageddosageformsareconductedbymeansof“real-time,”long-termtestsatspecifictemperaturesandrelativehumiditiesrepresentingstorageconditionsexperiencedinthedistributionchainoftheclimaticzone(s)ofthecountryorregionoftheworldconcerned.Labelingofthepackagedactivesubstanceordosageformshouldreflecttheeffectsoftemperature,relativehumidity,air,andlightonitsstability.Labeltemperaturestoragewarningswillbothreflecttheresultsofthereal-timestoragetestsandallowforexpectedseasonalexcursionsoftemperature.稳定性试验生产商必须通过合适的方法证明药物剂型的稳定性。如果各论中的含量测定法可以指示稳定性，那么它们就可以用于稳定性试验(即含量测定法能准确区分出完整的药物分子和它们的降解产物）。在考察药物的稳定性时，不仅应包括药典对其的要求，还应包括药物物理性状的改变，这些可以提示使用者药物的完整性是否有问题。按照规定时间点考察活性成分和药物制剂的稳定性。长期试验是在特定的温度、相对湿度条件下进行的，此条件代表销售此药品的相关国家或地区所在的气候带。已包装的活性成分或药物制剂的标签（Labeling）中应标明温度、相对湿度、空气和光照对它们的稳定性的影响。标签（Label）标识的贮存温度的要求不仅要考虑稳定性试验的结果，还要考虑到预期的季节性的温度偏差。ControlledRoomTemperatureControlledroomtemperature（seeStorageTemperatureandHumidityinPreservation,Packaging,Storage,andLabelingunderGeneralNoticesandRequirements）delineatestheallowabletoleranceinstoragecircumstancesatanylocationinthechainofdistribution（e.g.,pharmacies,hospitals,andwarehouses）.Thisterminologyalsoallowspatientsorconsumerstobecounseledastoappropriatestoragefortheproduct.Productsmaybelabeledeithertostoreat“Controlledroomtemperature”ortostoreattemperatures“upto25°”wherelabelingissupportedbylong-termstabilitystudiesatthedesignatedstorageconditionof25°.Controlledroomtemperaturelimitsthepermissibleexcursionstothoseconsistentwiththemaintenanceofameankinetictemperaturecalculatedtobenotmorethan25°.SeeMeanKineticTemperature.Thecommoninternationalguidelineforlong-termstabilitystudiesspecifies25±2°at60±5%relativehumidity.Acceleratedstudiesarespecifiedat40±2°andat75±5%relativehumidity.Acceleratedstudiesalsoallowtheinterpretationofdataandinformationonshort-termspikesinstorageconditionsinadditiontotheexcursionsallowedbycontrolledroomtemperature.Theterm“roomtemperature”isusedindifferentwaysindifferentcountries,andforproductstobeshippedoutsidethecontinentalU.S.itisusuallypreferableforproductlabelingtorefertoamaximumstoragetemperatureortemperaturerangeindegreesCelsius.受控的室温受控的室温（见通则和要求中保存，包装、贮存和标项下的贮存温度和湿度描述了药品销售地的贮存环境（如药房、医院和仓库）的允许偏差。这个术语建议病人或消费者在合适的条件贮存药物。药品的标签会标示贮存于“受控的室温”或者“不超过25度”，此贮存条件是由贮存于25度的长期稳定性研究得到的。受控的室温的允许偏差与平均运动温度一致，不超过25度。一般国际指导原则规定长期稳定性研究的条件为25±2°C，相对湿度60±5%。加速稳定性研究的条件为40±2C，相对湿度75±5%。除了受控室温允许的偏离外，加速试验也可提供关于贮存条件下短期偏移信息与数据的解释。药品要运输到北美大陆外的其他国家，在这些不同国家，术语“室温”有不同的表达方式。所以对于药品的标签来说，最好使用以摄氏度标明的最高贮存温度或温度范围。MeanKineticTemperatureMeanKineticTemperature（MKT）isdefinedasthesinglecalculatedtemperatureatwhichthetotalamountofdegradationoveraparticularperiodisequaltothesumoftheindividualdegradationsthatwouldoccuratvarioustemperatures.Thus,MKTmaybeconsideredasanisothermalstoragetemperaturethatsimulatesthenonisothermaleffectsofstoragetemperaturevariation.Itisnotasimplearithmeticmean.MKTiscalculatedfromtemperaturesinastoragefacility.ThetemperaturesforcalculatingMKTcanbeconvenientlycollectedusingelectronicdevicesthatmeasuretemperaturesatfrequentintervals(e.g.,every15minutes).MKTcanbecalculateddirectlyorthedatacanbedownloadedtoacomputerforprocessing.Fordispensingsites,suchaspharmaciesandhospitals,wheretheuseofsuchinstrumentsmaynotbefeasible,devicessuchashigh-lowthermometerscapableofindicatingweeklyhighandlowtemperaturesovera52-weekperiodmaybeemployed.ThearithmeticmeanoftheweeklyhighandlowtemperaturesisthenusedinthecalculationofMKT.MKTiscalculatedbythefollowingequation(derivedfromtheArrheniusequation):平均运动温度平均运动温度（MKT）定义为一个计算温度，一段时间内在这个温度药品的降解总量等于在贮存时不同温度药品降解的总和。因此，MKT可以被认为是等温的贮存温度，用它来模拟不等温的贮存温度变化。它并不是简单的算术平均°MKT是由一个贮存装置中测得的温度计算出来的。用来计算MKT的温度可以很容易通过电子设备测定出，此装置测定温度的间隔很短（例如：每15分钟）。可以使用电子设备直接计算MKT,也可以将数据下载到电脑中再计算。在配药的地方，例如药剂室或者医院，使用以上装置可能不太可行，但可以使用如高低温度测量设备这样的装置，它能测量出52周内的周最高和周最低温度。周最高和周最低温度的算术平均用于计算MKT。下列公式用于计算MKT（由阿仑尼乌斯方程推导出）：AH/Rln(e_0HRT1+e_0HRT2 e-^H/RTnninwhichTkisthemeankinetictemperature;DHistheheatofactivation,83.144kJ-mole1(unlessmoreaccurateinformationisavailablefromexperimentalstudies);Ristheuniversalgasconstant,8.3144x103kJ-mole1-degree1;T1isthevalueforthetemperaturerecordedduringthefirsttimeperiod,e.g.,thefirstweek;T2isthevalueforthetemperaturerecordedduringthesecondtimeperiod,e.g.,secondweek;andTnisthevalueforthetemperaturerecordedduringthenthtimeperiod,e.g.,nthweek,nbeingthetotalnumberofstoragetemperaturesrecorded(minimumof52weeklyentries)duringtheannualobservationperiod,[note—Alltemperatures,T,areabsolutetemperaturesindegreesKelvin(K).]ThefollowingisanexampleofatypicalstorageanddistributiontemperaturerangeinKelvindegreesandtheconversionfactorsusedtoconvertthisrangeintodegreesFahrenheitandCelsius.Kelvin(K)Fahrenheit(F)Celsius(C)288.1-303.159-8615-30ConversionFactors:FahrenheittoKelvin={[(F32)x5/9]+273.1}CelsiustoKelvin=273.1+CFahrenheittoCelsius=[(F32)x5/9]公式中Tk代表平均动力温度；/H代表激活的热能，83.144KJ.mole-1(除非从试验研究中能得到更精确的信息)；R代表气体常数，8.3144X10-3KJ.mole-1,degree-1；T1为第一时间段记录的温度数值，例如，第一周；T2为第二时间段记录的温度数值，例如，第二周；Tn为第n时间段记录的温度数值，例如，第n周，n为记录的贮存温度的总数(每周一次记录，在每年的监测周期内最小为52次)【注释:所有温度T，为绝对温度，单位为开尔文(K)。】下面是典型的贮存和流通温度范围的例子(单位为开尔文)，通过转换因子将此范围转换为华氏温度和摄氏度范围。Kelvin(K) Fahrenheit(°F) Celsius(°C)288.1-303.1 59-86 15-30转换公式:华氏温度转换为开尔文={[(°F—32)X5/9]+273.1}摄氏温度转换为开尔文=273.1+C华氏温度转换为摄氏温度=[(F—32)X5/9]ClimaticZonesForconvenienceinplanningforpackagingandstorage,andforstabilitystudies,internationalpracticeidentifiesfourclimaticzones,whicharedescribedinTable1.TheUnitedStates,Europe,andJapanarecharacterizedbyzonesIandII.ThevaluesinTable1arebasedonobservedtemperaturesandrelativehumidities,bothoutsideandinrooms,fromwhichmeankinetictemperaturesandaveragehumidityvaluesarecalculated.1Derivedvaluesarebasedoninspectionofdatafromindividualcitiesandonallowancesforamarginofsafetyinassignmentofthesespecifiedconditions.大Datarecordedas<19°calculatedas19°.大大Calculatedmeankinetict