藥物穩(wěn)定性實(shí)驗(yàn)

1150藥物穩(wěn)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.就藥物制劑而言，術(shù)語(yǔ)“穩(wěn)定性”是指單位劑量藥物理化性質(zhì)的完整程度以及在適當(dāng)情況下對(duì)微生物污染的抵抗能力。制劑的有效期指從生產(chǎn)至失效期的期限。在有效期內(nèi)，產(chǎn)品須符合各論中有關(guān)鑒別、效價(jià)、質(zhì)量和純度的規(guī)定。藥物制劑的穩(wěn)定性參數(shù)可能受到它所貯存的環(huán)境(溫度、光照、空氣和濕度)的影響，還受到包裝材料的影響。藥典收載的藥物制劑的標(biāo)簽應(yīng)標(biāo)明貯存條件。在有效期內(nèi)，藥品應(yīng)在規(guī)定的各條件下貯存。藥品在分銷過(guò)程中(即從藥品離開(kāi)生產(chǎn)商后直到由配藥員處理或銷售者賣給消費(fèi)者)必須遵守標(biāo)簽上規(guī)定的貯存要求。盡管對(duì)于消費(fèi)者來(lái)說(shuō)藥品標(biāo)簽應(yīng)標(biāo)明合適的貯存條件，但是藥品在由配藥員或銷售者到達(dá)消費(fèi)者手中時(shí)，對(duì)貯存環(huán)境的控制是很困難的。藥品的失效期應(yīng)在容器標(biāo)簽上注明。StabilityProtocolsStabilityofmanufactureddosageformsmustbedemonstratedbythemanufacturer,usingmethodsadequateforthepurpose.Monographassaysmaybeusedforstabilitytestingiftheyarestability-indicating(i.e.,iftheyaccuratelydifferentiatebetweentheintactdrugmoleculesandtheirdegradationproducts).Stabilityconsiderationsshouldincludenotonlythespecificcompendialrequirements,butalsochangesinphysicalappearanceoftheproductthatwouldwarnusersthattheproduct'scontinuedintegrityisquestionable.Stabilitystudiesonactivesubstancesandpackageddosageformsareconductedbymeansof“real-time,”long-termtestsatspecifictemperaturesandrelativehumiditiesrepresentingstorageconditionsexperiencedinthedistributionchainoftheclimaticzone(s)ofthecountryorregionoftheworldconcerned.Labelingofthepackagedactivesubstanceordosageformshouldreflecttheeffectsoftemperature,relativehumidity,air,andlightonitsstability.Labeltemperaturestoragewarningswillbothreflecttheresultsofthereal-timestoragetestsandallowforexpectedseasonalexcursionsoftemperature.穩(wěn)定性試驗(yàn)生產(chǎn)商必須通過(guò)合適的方法證明藥物劑型的穩(wěn)定性。如果各論中的含量測(cè)定法可以指示穩(wěn)定性，那么它們就可以用于穩(wěn)定性試驗(yàn)(即含量測(cè)定法能準(zhǔn)確區(qū)分出完整的藥物分子和它們的降解產(chǎn)物）。在考察藥物的穩(wěn)定性時(shí)，不僅應(yīng)包括藥典對(duì)其的要求，還應(yīng)包括藥物物理性狀的改變，這些可以提示使用者藥物的完整性是否有問(wèn)題。按照規(guī)定時(shí)間點(diǎn)考察活性成分和藥物制劑的穩(wěn)定性。長(zhǎng)期試驗(yàn)是在特定的溫度、相對(duì)濕度條件下進(jìn)行的，此條件代表銷售此藥品的相關(guān)國(guó)家或地區(qū)所在的氣候帶。已包裝的活性成分或藥物制劑的標(biāo)簽（Labeling）中應(yīng)標(biāo)明溫度、相對(duì)濕度、空氣和光照對(duì)它們的穩(wěn)定性的影響。標(biāo)簽（Label）標(biāo)識(shí)的貯存溫度的要求不僅要考慮穩(wěn)定性試驗(yàn)的結(jié)果，還要考慮到預(yù)期的季節(jié)性的溫度偏差。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.受控的室溫受控的室溫（見(jiàn)通則和要求中保存，包裝、貯存和標(biāo)項(xiàng)下的貯存溫度和濕度描述了藥品銷售地的貯存環(huán)境（如藥房、醫(yī)院和倉(cāng)庫(kù)）的允許偏差。這個(gè)術(shù)語(yǔ)建議病人或消費(fèi)者在合適的條件貯存藥物。藥品的標(biāo)簽會(huì)標(biāo)示貯存于“受控的室溫”或者“不超過(guò)25度”，此貯存條件是由貯存于25度的長(zhǎng)期穩(wěn)定性研究得到的。受控的室溫的允許偏差與平均運(yùn)動(dòng)溫度一致，不超過(guò)25度。一般國(guó)際指導(dǎo)原則規(guī)定長(zhǎng)期穩(wěn)定性研究的條件為25±2°C，相對(duì)濕度60±5%。加速穩(wěn)定性研究的條件為40±2C，相對(duì)濕度75±5%。除了受控室溫允許的偏離外，加速試驗(yàn)也可提供關(guān)于貯存條件下短期偏移信息與數(shù)據(jù)的解釋。藥品要運(yùn)輸?shù)奖泵来箨懲獾钠渌麌?guó)家，在這些不同國(guó)家，術(shù)語(yǔ)“室溫”有不同的表達(dá)方式。所以對(duì)于藥品的標(biāo)簽來(lái)說(shuō)，最好使用以攝氏度標(biāo)明的最高貯存溫度或溫度范圍。MeanKineticTemperatureMeanKineticTemperature（MKT）isdefinedasthesinglecalculatedtemperatureatwhichthetotalamountofdegradationoveraparticularperiodisequaltothesumoftheindividualdegradationsthatwouldoccuratvarioustemperatures.Thus,MKTmaybeconsideredasanisothermalstoragetemperaturethatsimulatesthenonisothermaleffectsofstoragetemperaturevariation.Itisnotasimplearithmeticmean.MKTiscalculatedfromtemperaturesinastoragefacility.ThetemperaturesforcalculatingMKTcanbeconvenientlycollectedusingelectronicdevicesthatmeasuretemperaturesatfrequentintervals(e.g.,every15minutes).MKTcanbecalculateddirectlyorthedatacanbedownloadedtoacomputerforprocessing.Fordispensingsites,suchaspharmaciesandhospitals,wheretheuseofsuchinstrumentsmaynotbefeasible,devicessuchashigh-lowthermometerscapableofindicatingweeklyhighandlowtemperaturesovera52-weekperiodmaybeemployed.ThearithmeticmeanoftheweeklyhighandlowtemperaturesisthenusedinthecalculationofMKT.MKTiscalculatedbythefollowingequation(derivedfromtheArrheniusequation):平均運(yùn)動(dòng)溫度平均運(yùn)動(dòng)溫度（MKT）定義為一個(gè)計(jì)算溫度，一段時(shí)間內(nèi)在這個(gè)溫度藥品的降解總量等于在貯存時(shí)不同溫度藥品降解的總和。因此，MKT可以被認(rèn)為是等溫的貯存溫度，用它來(lái)模擬不等溫的貯存溫度變化。它并不是簡(jiǎn)單的算術(shù)平均°MKT是由一個(gè)貯存裝置中測(cè)得的溫度計(jì)算出來(lái)的。用來(lái)計(jì)算MKT的溫度可以很容易通過(guò)電子設(shè)備測(cè)定出，此裝置測(cè)定溫度的間隔很短（例如：每15分鐘）?？梢允褂秒娮釉O(shè)備直接計(jì)算MKT,也可以將數(shù)據(jù)下載到電腦中再計(jì)算。在配藥的地方，例如藥劑室或者醫(yī)院，使用以上裝置可能不太可行，但可以使用如高低溫度測(cè)量設(shè)備這樣的裝置，它能測(cè)量出52周內(nèi)的周最高和周最低溫度。周最高和周最低溫度的算術(shù)平均用于計(jì)算MKT。下列公式用于計(jì)算MKT（由阿侖尼烏斯方程推導(dǎo)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代表平均動(dòng)力溫度；/H代表激活的熱能，83.144KJ.mole-1(除非從試驗(yàn)研究中能得到更精確的信息)；R代表氣體常數(shù)，8.3144X10-3KJ.mole-1,degree-1；T1為第一時(shí)間段記錄的溫度數(shù)值，例如，第一周；T2為第二時(shí)間段記錄的溫度數(shù)值，例如，第二周；Tn為第n時(shí)間段記錄的溫度數(shù)值，例如，第n周，n為記錄的貯存溫度的總數(shù)(每周一次記錄，在每年的監(jiān)測(cè)周期內(nèi)最小為52次)【注釋:所有溫度T，為絕對(duì)溫度，單位為開(kāi)爾文(K)?！肯旅媸堑湫偷馁A存和流通溫度范圍的例子(單位為開(kāi)爾文)，通過(guò)轉(zhuǎn)換因子將此范圍轉(zhuǎn)換為華氏溫度和攝氏度范圍。Kelvin(K) Fahrenheit(°F) Celsius(°C)288.1-303.1 59-86 15-30轉(zhuǎn)換公式:華氏溫度轉(zhuǎn)換為開(kāi)爾文={[(°F—32)X5/9]+273.1}攝氏溫度轉(zhuǎn)換為開(kāi)爾文=273.1+C華氏溫度轉(zhuǎn)換為攝氏溫度=[(F—32)X5/9]ClimaticZonesForconvenienceinplanningforpackagingandstorage,andforstabilitystudies,internationalpracticeidentifiesfourclimaticzones,whicharedescribedinTable1.TheUnitedStates,Europe,andJapanarecharacterizedbyzonesIandII.ThevaluesinTable1arebasedonobservedtemperaturesandrelativehumidities,bothoutsideandinrooms,fromwhichmeankinetictemperaturesandaveragehumidityvaluesarecalculated.1Derivedvaluesarebasedoninspectionofdatafromindividualcitiesandonallowancesforamarginofsafetyinassignmentofthesespecifiedconditions.大Datarecordedas<19°calculatedas19°.大大Calculatedmeankinetict