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Drug stability

1. DRUGSTABILITY
MRS.M.S.BINDU

2. INTRODUCTION
STABILITY:
definesstabilityofpharmaceuticalproductas,
“extenttowhichaproductretainswithinspecified
limitsandthroughoutitsperiodofstorageanduse
(i.e.shelflife).
Thecapacityorthecapabilityofaparticular
formulationinaspecificcontainertoremainwithin
particular chemical,microbiological,
therapeutically,andtoxicologicalspecifications.
2

3. Drugstabilityisdefinedastheabilityofthe
pharmaceuticaldosageformtomaintainthe
physical,chemical,therapeuticandmicrobial
propertiesduringthetimeofstorageandusageby
3
the
Thepurposeofstabilitystudies
patient.
istoprovide
evidenceonhowthequalityoftheactive
substanceorpharmaceuticalproductvarieswith
timeundertheinfluence
environmentalfactor
such
ofavarietyof
astemperature,
humidityandlight
DRUGSTABILITY

4. IMPORTANCE
Chemicalandphysicaldegradationofdrugsubstancesmay
changetheirpharmacologicaleffects,whichisthenaffectingon
theirtherapeuticandtoxicologicaleffect.
Pharmaceuticalsproductsareusedtherapeuticallybasedon
theirefficacyandsafety,theyshouldbestable.
Maintenanceofqualityuntilthetimeofusageoruntiltheir
expirationdate.
Thequalityshouldbemaintainedunderthevariousconditions
thatpharmaceuticalsencounter,duringproduction,storage
inwarehouses,transportationandstorageinhospitalsas
wellasinthehome.
4

5. NEED
5

6. Wherestability studiestakesplace.......
Drugdiscoverydevelopment
6

7. Typesofstability
7

8. TYPESOFSTABILITYTESTING
SR.
NO
.
STUDY STORAGE
CONDITION
TESTING
TIMING
(MONTH)
MinimumTime
PeriodCovered
ByDataAt
Submission
1 LONGTERM 25ºC±2ºC0,3,6,9,12,12months
(Ambient) 60%RH±5%18,24,36,48,
60.
2INTERMEDIATE
(controlled)
30ºC±2ºC
60%RH±5%
0,3,6,9,12. 6months
3 ACCELERATED
(Shortterm)
40ºC±2ºC
75%RH±5%
0,1,2,3,6,9. 6months
9

9. DEGRADATIONPATHWAYS
9
Degradationofactivedrugleadstoloweringofquantityof
thetherapeuticagentinthedosageform
Atoxicproductformationmaytakesplacedueto
decompositioninstabilityofdrugproductcanleadto
adecreaseinitsBIOAVAILABILITY.
ChangesinPHYSICAL APPEARANCE ofgiven
dosageformmaytakesplace.
DegradationmayincreaseordecreasethePOTENCY
ofdrug.

10. TYPESOFDEGRADATIONPATHWAYS
10

11. PHYSICALDEGRADATION
11
LOSSOFVOLATILECOMPOUNDS
LOSSOFWATERABSORPTIONOFWATER
CRYSTALGROWTHPOLYMORPHISMS
COLOURCHANGESPHOTOLYSIS

12. LOSSOFVOLATILECOMPOUNDS
12
Someofvolatilecomponentsalcohol,ether,Iodine,
volatileoils,Camphormentholetcescapefromthe
formulationsexposéthemdegraded.
EXAMPLE:
Sometypesoftablets(Nitroglycerinetablets)Aromatic
water
PREVENTION:
inwell
closed
Suchproductshouldbeplaced
container.
Temperatureshouldbeproper.

13. LOSSOFWATER
13
Waterlossfromliquidpreparation(o/wemulsion)leads
tochangesinstability.Itcausescrystallizationofdrug
product.
whichmayleadtoincreaseinpotency,anddecreasein
weight.
EXAMPLE:
Waterevaporatesfromna2so4.BORAX.
Creams:especiallyoil/water,theybecomedrybyloss
ofwater.
PREVENTION:
Productsshouldbeplacedinwell-closedcontainer.

14. ABSORPTIONOFWATER
Hygroscopicdrugsabsorbthewaterfromexternal
atmospherecausingthephysicaldegradation.
Effervescentpowdersandtabletswilldeteriorateif
storedinamoistatmosphere.
EXAMPLE:
Powders:Liquificationanddegradationmayoccurasa
resultofabsorptionofwater
Suppositorieswhichbasemadefromhydrophilic
substancesasGlycerin,Gelatin,andpolyethyleneglycol.
Theconsistencyoftheseformsbecomesjelly-like
appearance.
PREVENTION:
Productsshouldbeplacedinwell-closedcontainer
andindryplace.
14

15. Drugswhenloosewater,becomesaturatedand
crystalgrowthoccurs.
Crystallizationisenhancedinporoustablets.In
solutionsaftersupersaturationcrystalgrowthoccurs.
EXAMPLE:
Injectionofcalciumglucconate
Insuspensionscrystalssettledownandcakingoccursandsuspension
becomesunstable.
Ophthalmicpreparations.
PREVENTION:
SOLUTIONS-Stabilizersareadded
SUSPENSION-
·Incorporationofsurfaceactiveagent
·Byincreasingviscosityofsuspendingmaterial
15
CRYSTALGROWTH

16. Polymorphsshowsignificantdifferencesin
importantphysiochemicalpropertiessuchas
solubility,dissolutionrateandmeltingpoint.In
polymorphicchangescrystalformsarechanged.
Thismaycausechangeinsolubilityandpossibly
crystallinegrowthinaqueoussuspension.
EXAMPLE:
Cortisoneacetatesuspension.
•PREVENTION:
suspension–suspendingagentlikemethyl
cellulose&ethylcellulose
POLYMORPHISMS
17

17. Whenmoleculesareexposedtoelectromagnetic
radiationtheyabsorblight(photons)atcharacteristic
wavelengthwhichcauseincreaseinenergywhichcan
causedecomposition.
EXAMPLE:
Sodiumnitroprusideinaqueoussolution(whichis
administeredbyIVinfusionformanagementofacute
hypertension).
Iodine
PREVENTION:
Useofambercoloredbottles.
Storingtheproductindark,packagingincartonsalso
actasphysicalbarriertolight.
19/11/2016 17
PHOTOLYSIS

18. Colourchangesindicatechemicalor
decompositionoftheactiveingredients,
ingredients.Colourchangesareof
photochemical
dyesorother
twotypes.
1)Lossofcolour
2)Developmentofcolour
EXAMPLE:
COLOURCHANGES
•PhenolphthaleincolorchangesasthePHchanges.It
iscolorlessinacidicsolutionandpink
inbasic.
•ascorbicacidtabletturnyellowishbrown.
•PREVENTION:
•Protecttheproductfromlightandair
•Avoidtheusingreducingsubstancesasadditives.
18

19. CHEMICALDEGRADATION
19

20. 2
HYDROLYSIS
21

21. -InvolveAcyl–AcidCleavage.
EXAMPLE:
aspirin,atropine,physostigmine&procaine..
REACTION:
21

22. •Amidebondsarelesssusceptibletohydrolysis
thanesterbonds.
•Theleavinggroup,anamine,isapoorerleaving
group.Itinvolvescleavageofamidelinkagetogive
anamineinsteadofalcoholasincaseofesters.
EXAMPLE:
Chloramphenicol,Barbiturates
REACTION:
RCONHR(amide)+H2O RCOOH+NH2-R(AMINE)
22

23. •Barbiturates,hydantoins,andimidescontain
functionalgroupsrelatedtoamidesbuthavea
tendencytobemorereactive.
•Barbituricacidssuchasbarbital,phenobarbitaland
amobarbital,undergoring-openinghydrolysis.
REACTION:
23

24. •Benzodiazepinessuchasdiazepam,oxazepam,and
nitrazepamundergoringopeningduetoreversible
hydrolysisoftheamideandazomethinebonds.
•Benzodiazepinoxazoles(oxazole-condensed
benzodiazepines)suchasoxazolam,flutazolam,
haloxazolam,andcloxazolamareundergoring
openingduetohydrolysis.
REACTION:
24

25. 25

26. ISOMERIZATION
27

27. RACEMIZATIO
N
Racemizationreferstopartial
conversionofoneenantiomerinto
another.Itinvolvestheopticallyactive
formofadrugintoitsenantiomorph.
27

28. EPIMERIZATIO
N
Itoccurswiththecompoundhavingmore
thanoneasymetriccarbonatominthe
molecule.Atequilibrium,bothepimersare
present,butnotinequalproportion.
EXAMPLE:
Underprolongedstorage solution
containingergometrineisdecomposedby
hydrolysisand isomerizedto
ergometrinine
28

29. DECARBOXYLATIO
N
EliminationofCO2fromcompound.Drug
substanceshavingacarboxylicacid
groupissometimessusceptibleto
decarboxylation,
EXAMPLE:
4-Aminosalicylicacidprocain
29

30. ELIMINATIO
N
Inelimination,reactionsomegroupsof
thesubstanceiseliminated.
EXAMPLE:
Trimelamol eliminates its
hydroxymethylgroupsandforms
formaldehyde.
30

31. OXIDATIO
N
Removalofanelectropositiveatom,radicalor
electron,ortheadditionofanelectronegative
atomorradical.Oxidationiscontrolledby
environmenti.e.,light,traceelements,oxygen
andoxidizingagent.
31

32. TYPESof
OXIDATION
•Oxidationinwhichtheoxygenpresents
intheairisinvolved.Thisprocess
proceedsslowlyundertheinfluenceof
atmosphericoxygen.
•Oxidationinwhichremovalofthe
electronisinvolvedwithoutpresenceof
O2.
32

33. PREVENTIO
N
Chelating
agent
Antioxidant
agent
33

34. Therateofreactionisfrequentlyinfluencedbythe
presenceofcatalyst.
i.e.Hydrolysisofsucroseinofwaterwithhyrogenionsas
catalyst.
Twotypes
1.Specificacidbasecatalysis:Whentheratelawofan
equationinvolveschangeintheconcnetrationof
hydrogenorhydroxylionsthereactionissaidtobe
specificacidbasecatalysis.
2.Generalacidbasecatalysis:InadditiontotheeffectofpH
onthereactionrate,theremaybecatalysisbyoneofthe
morespeciesofbuffer,thisiscalledgeneralacidbase
catalysis.Theeffectofthebuffercomponentscanbe
large.Forexample,thehydrolysisrateofcodeinein
0.05MphosphatebufferatpH7isalmost20times
fasterthaninunbufferedsolutionatthispH.
AcidBaseCatalyst
M.S.Bindu,MMCOPThergaonPune.For
privatecirculationonly
34

35. MICROBIAL
DEGRADATION
Contaminationofaproductmaysometimescausealotof
damageandsometimesmaynotbeanythingatall.
-Thusitisdependentonthetypeofmicrobeanditslevelof
toxicityitmayproduces.
-Ifparenteralsorophthalmicformulationsarecontaminated,
itmaycauseseriousharm.
35

36. Sourceof
microbial
contamination
Water&
air
Container&
closure
Raw
material
36

37. PREVENTIO
N
Suitablydesigningthecontainers
UsuallyusingsingledosecontainersStickingto
properstorageconditions
antimicrobial substanceas
37
Addingan
preservative

38. THERAPEUTIC
DEGRADATION
Therapeuticeffectmustbechangedduetohydrolysis,
isomerisationorepimerization.
Example:Adrenaline
38

39. Toxicological
degradation
39

40. Kineticstability
Kineticsdealswiththestudyoftherateatwhichprocesses
occurandmechanismofchemicalreactionsItinvolvesthe
studyofrateofchangeandthewayinwhichthisrateis
influencedbytheconcentrationofreactants,products,and
otherchemicalspeciesthatmaybepresent,andbyfactors
suchassolvents,pressure,andtemperature.
Kineticsappliesto:StabilityIncompatibilityDissolution
AbsorptionDistribution
Drugactionatmolecularlevel
Eliminationprocesses
40

41. Rate&orderofreaction
•Thespeedorvelocityofareactionwithwhich
areactantorreactantsundergoesachange.
•Itisdeterminedbythechangeinthe
concentrationofthereactantsorproductsasa
functionoftime.
Rate
•Thenumberofconcentrationsthatdetermine
rate.
•The way in which the
concentration ofthereactant
influencestherate.
Orderof
reaction
41

42. Typesoforderof
reaction
•Rateisconstantandisindependent
oftheconcentration ofanyofthe
reactants.
Zeroorderof
reaction
•Thereaction rateofchangeis
proportionaltodrugconcentration.
Firstorderof
reaction
•Ratedependsontheproductoftwo
concentration terms.Whenyouhavetwo
componentsreactingwitheachotheroronecomponent
reactingwithitself.
Secondorderof
reaction
Pseudoorderof
reaction
•Forsomereactions,therateofthereactionmaybe
independentoftheconcentrationofoneormoreofthe
reactingspeciesoverawiderangeofreactions.
42

43. Shelflife
43
Itisdefinedasthetimerequiredforthe
concentrationofthereactanttoreduceto90%of
itsinitialconcentration.
Representedast90
theunitsoftime/conc.
t90=(a-0.9a)/ko=0.1a/ko
Where,
a=initialconcentration.
ko=specificrateconstantforzeroorderreaction.

44. Shelflife
44

45. SOLUTION
STABILITY
45
Themainpurposeofsolutionstabilityisidentificationof
conditionsnecessarytoformastablesolutionStudy.
Includes–effectsofpH,Ionicstrength,Co-solvent,light
,temperatureandoxygen
InterestedexperimentsatextremesconditionsofpHand
temperature(0.01NHCl,water,0.01N,NaOHallat90°C).
Aq.Buffersareusedtoprovidewiderangewith
constantlevelsofdrug,cosolventandionicstrength
Compatiblewithphysiologicalmedia

46. SOLIDSTATESTABILITY
46
Thepurposeofsolidstatestabilityisidentificationsofstable
storageconditionsfordruginthesolidstateandidentification
ofcompatibleexcipientsforaformulations.
Affectedbychangeinpurityandcrystallinity
Initialbulklotsandnewerlots–tobestudied
Solidstateissloweranddifficulttointerpretthan
solutionstate
TLC,UV-Vis,fluorescence
Polymorphicchanges–DSC,IRorappearance
changeslikeoxidation–surfacediscoloration

47. pHSTABILITYSTUDIES
19/11/2016 47
ThepH-stabilityprofileisessentialfor
understandinghowthecompoundbehavesin
differentenvironmentsandinformsformulation
development,processdevelopment,drugproduct
stabilityandtherouteofadministrationofthe
molecule.
TodevelopapH-stabilityprofile,itisimportantto
developstability-indicatingassaysfortheintact
drugatthevariouspHvaluestobestudied.

48. pH-stabilitystudies
48

49. CONCLUSION
49
Pharmaceuticalproductsareassignedashelflifewhich
determinesthetimewhenaproductisconsideredtobe
safeandeffectiveunderstoragecondition.
Stabilitystudiesshouldbebasedonthebasisof
pharmaceuticalR&Dandregulatoryrequirements.
Degradationstudiesrevealtheintrinsicchemicalpropertiesof
theAPIwhileformalstabilitystudiesestablishtheretestdate.
Theshelflifeisderivedfromstabilitystudies

50. 50