9.LIMIT TESTS Revised.ppt

Tests that are used in pharmaceutical analysis

1. By BisetA.
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2. Outline
Introductiontolimittest
Explainthetypesoflimittest
Generalimpuritylimittest
Specificimpuriitylimittest
Describethelimittestforashvalues
Describethelimittestformoistureorwatercontent
Describetheprocedureforheavymetallimittest
Describethelimittestforacidradicals
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3. Purity
Thedrugshouldbephysically&chemicallypure.
Purityisthestateofachemicalcompoundwhennoimpurity
canbedetectedorcompletefreedomfromextraneousmatter.
Thestandardizationof‘pharmaceuticalchemicals’andthe
dosageformspreparedtherefromplaysavitalrole.
Sothatthepatientgetsthe‘drug’withinthepermissible
limitsofpotencyandtolerance.
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4. Drugsshould:
Attainthehighestattainablestandardsofpurity
Elicitthedesiredbiologicalresponse
Biologicalresponseofpharmaceuticalsubstancesholdsequal
importance
Likethatofchemicalpurity
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5. Impurities:
Impurities
AreunwantedchemicalspresentintheAPI
Canneverbeeliminated
Havenotherapeuticvalue
Arepotentiallyharmful
Thetotalimpuritiesshouldbeincertainminimalrange
i.e.thereshouldbeacceptancecriteriaforspecified
impurities.
Thereforetheyneedtobecontrolled.
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6. Cont…
Thepurityofpharmaceuticalscanbeascertainedthrough
puritytest.
Thetestsforpurityinvolve:
Testsforthepresenceofimpurity----Identificationtest
Fixthelimitsoftolerancefortheseimpurities---Quantificationtest
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7. Themethodshouldbe:
Specific-selectivereactionwiththetraceimpurity
Sensitive-yieldreproducibleresults
Themethods:
Generallimittest
Specificlimittest
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8. 1.General Impurity limit tests
Fornon-specificimpurities
Clarityofsolution
Measurementismadebydirectcomparisonwitha
referencesolution
Solutionsarecleariftheirclarityisthesameasthatof
waterorthesolventused
e.g.Solutionsforinjectionsshouldbereasonablyfree
fromparticulatematter.
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9. General limit tests…
Colorofsolution
Asolutionmaybedescribedascolorlessifithastheappearanceas:
Wateror
Thesolventemployedinthepreparationofthesolutionbeingexamined
Insolublematter
Thelimittestisusedtocontrolsmallamountsofsolvent-insoluble
contamination.
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10. Moisture,Volatilematterandresidualsolvents
Anumberofpharmaceuticalsubstancesusuallyabsorbmoistureon
storagetherebycausingdeterioration.
Suchdeteriorationofhygroscopicsubstancesislimitedbyarequirement
forthelossinweight(lossondrying).
Whenthesubstanceissubjectedtodryingunderspecifiedconditions
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General limit tests…

11. Non-volatilematter
Theselimitsareappliedtosubstanceswhicharereadily
volatile
Tocontrolimpuritiessuchasdustinvolatilesubstances
Eg.halothane,anaestheticetherandhydrogenperoxide
solution.
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General limit tests…

12. Residueonignition
Limitstheamountofresidueremainedafterthesubstanceis
ignited.
Applicabletothefftwocategoriesofpharmaceutical
substances:
Thosewhicharecompletelyvolatilewhenignitede.g.,Hg.
Thosewhichundergototaldecompositiontherebyleavinga
residuewithadefinitecomposition
e.g.Calamine—abasiczinccarbonatethatgivesriseto
ZnOastheresidue.
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General limit tests…

13. Loss on ignition
Generallyappliedtorelativelystablepharmaceuticalsubstancesthat
arelikelytocontainthermolabileimpurities.
E.g.Fromofficialcompendia
Pharmaceutical Ignition Ignition Prescribed
Substance Temp. (°C) Time Limits(%)
Magnesium Trisilicate 900 TCW 17.0-34.0
Magnesium Sulphate450-500 TCW 31.0-34.0
TCW-To Constant Weight
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General limit tests…

14. Ashvalues
Inorganicresidueremainingafterincineration.
Showtheamountofinorganicsubstancespresentincrudedrugs.
Theashvaluesareapplied:
Toensuretheabsenceofanextraneousmineralmatter
Todetectadulteration
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General limit tests…

15. 2.Limit tests for specific impurities
limitationisplacedforphysiologicallyharmfulimpurities.
LimitTestsforMetallicImpurities
E.g.Thecontroloftoxicelements(As,Sb,Pb,Cd,Hg)
Specifictestsforacidradicalimpurities
Themostcommonacidradicalimpuritiesarechloride&sulphate
Alsoappliedforanumberofotheracidradicalcontaminants
Cyanide,Oxalate,PhosphateandSilicate
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16. Limitsonashvalues
Theashvaluesusuallyrepresenttheinorganicresiduepresent
inofficialherbaldrugsandpharmaceuticalsubstances.
Thesevaluesarecategorizedintofourheads:
(a)AshValue(TotalAsh)
(b)Acid-InsolubleAsh
(c)SulphatedAsh
(d)Water-SolubleAsh
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Limit tests for specific impurities…

17. i.AshValue(TotalAsh)
Ashvaluenormallydesignatesthepresenceofinorganicsalts
E.g.,calciumoxalatefoundnaturallyinthedrug
Inorganicmatterderivedfromexternalsources
ii.Acid-InsolubleAsh
Designedtomeasuretheamountofashinsolubleto
dilutedhydrochloricacid.
Bytreatingthe‘totalash’withacid
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Limit tests for specific impurities…

18. iii.SulphatedAsh
Itisdeterminedbyadoubleignitionwithconc.H2SO4,
metalsthusremainassulphidesthatarestabletoheat.
Theestimationof‘sulphatedash’isbroadlyemployedin
thecaseof:
e.g.ActivatedCharcoal,NMT:5.00%
Griseofulvin,NMT:0.10%
Ascorbicacid,NMT:0.1%
CephalexinNMT:0.20%
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Limit tests for specific impurities…

19. iv.Water-SolubleAsh
Water-solubleashisspecificallyusefulindetectingsuch
sampleswhichhavebeenextractedwithwater.
Atypicalexampleofanofficialdrugisthatof‘Ginger’,the
water-solubleashofwhichisfoundtobenotmorethan
6.0%.
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Limit tests for specific impurities…

20. iv.Limitsonmoisturecontent
Moistureplaysremarkablenegativeroleinpharmaceutical
product,particularlyforsoliddosageforms.
Bothphysicalandchemicalstabilityofsomedrugsareaffected
bymoisture.
Moistureisabsorbedonthesurfaceofsoliddrugsandincreases
therateofdecomposition.
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Limit tests for specific impurities…

21. Presenceofmoisturepossessesacriticalchallengeondrug
stability.
Moistureaccelerates:
Thehydrolysisofdrug
Facilitatesreactionwithotherexcipients
Affectingstabilityandshelflifeofthefinalproduct.
Therefore,itisimportanttospecifylimitsofmoisture
content.
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Limit tests for specific impurities…

22. Cont…
Methodsofmoisturecontentdetermination
Lossondryingmethod
Karl-Fischertitrationmethod
Othermethods
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23. A.Loss on drying method
Itisthelossofweightin%w/wresultingfromwater&
volatilemattersthatarelostunderspecifiedconditions.
Reflectsthenetweightofapharmaceuticalsubstance
beingdriedataspecifiedtempeitheratanatmospheric
orunderreducedpressure.
Advantages
Easytouse,Relativelyrapid
Manysamplescanbeanalyzedsimultaneously
Disadvantages-Destructive,Timeconsuming
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24. B .Karl Fischer Method
TheWaterDeterminationTest(KFMethod)isdesignedto
determinewatercontentinsolidsubstances
UtilizingthequantitativereactionofwaterwithKFreagent.
KFreagentwhichiscomposedofiodine,sulphurdioxide,
pyridineandmethanol.
WaterpresentintheanalytereactswiththeKFreagentas
shownbelow:
2432553355
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.)(.
.)(23
OCHSOOHNHCOHCHSONHC
SONHCIHNHCNHCSOIOH







25. Onemoleculeofiodinedisappearsagainsteachmoleculeof
waterpresentinthegivensample.
Therearetwodeterminationmethods:
Volumetrictitrationmethod
Coulometrictitrationmethod
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Karl Fischer Method …

26. TheendpointinaKarlFishertitrationcanbelocatedinseveralways.
1.Visualdetection
Beforetheendpointthesolutionisyellow
Aftertheendpointthefirstexcessofthereagentimpartsthe
characteristicbrownI
2color
2.Coulometricdetection
currentshalltendtoflowtillfreeiodineexists,toremovehydrogen
andultimatelydepolarizethecathode.
Asituationwillsoonarisewhenpracticallyallthetracesofiodine
havereactedcompletelytherebysettingthecurrenttoalmost
zeroorveryclosetozeroorattaintheend-point.
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Karl Fischer Method …

27. Thank you
!!!
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