effect of various environment and processing on stability of formulations

1. Effect of
various environment/processing on stability of
the formulation and techniques for
stabilization of products against the same
Seminar submitted to:-
Mr.AfrasimMoinKhan,
Dept. of Pharmaceutics,
JSSCP, Mysore.
submitted by:-
T.ManojKumar,
Final year B.Pharm.

2. .
•All medical agents are to be investigated for their
decomposition before being marketed.
•Most drugs contain one or more functional groups and
therefore may undergo different chemical reactions.
•Ingredients present in dosage forms and environmental
factors affect the physical and chemical stability of of
drugs, such as –
–Moisture
–Heat
–Light
–Radiation etc.,

3. PHYSICAL DEGRADATION OF
PHARMACEUTICAL PRODUCTS
-preventive measures

4. Loss of volatile constituents :-
Medicinalagentssuchasiodine,camphor,menthol,ethylalcohol,
anestheticether,chloroformhaveatendencytoevaporatefromthe
productduringstorage.
Similarly,nitroglycerinetabletsmaylooseitspotencyowingto
volatilisationofthemedicament.
Thepreventivemeasuresincludekeepingtheproductinwell-closed
containers,andstoringitincoolplace.
Lossofwater:-
Lossofvehicle(water)fromtheproductleadstodecreaseinweight,
risesinconcentrationofdrugandincreasepotency.
Efflorescentsubstances,suchasborax,caffeineandquinidine
sulphate,haveanaturaltendencytoloosewater.
Productssuchasemulsionsandsemisolidsexhibitcracking.
Lossofwaterdependsontemperatureandhumidity.
Preventivemeasuresincludepreservingtheproductinawell-closed
containerandstoringitinacoolplace.

5. Absorption of water :-
Absorptionofmoisturefromtheatmosphereincreasetheweightof
theproduct,dilutesthedose,anddecreasesthepotency.
Deliquescentsubstances,suchascalciumchlorideandpotassium
chloridehaveanaturaltendencytoabsorbwater.Gelatincapsules
willabsorbmoistureandbecomesoftandsticky.
Preventivemeasuresincludestorageofsuchproductsinwell-closed
containers.
Crystalgrowth:-Fluctuationsintheambienttemperature(day&night
orseasonal)causecrystalgrowth.
Solutions-whentemperatureislowered,thesolutionbecomes
supersaturated.Hence,precipitation&crystalgrowthofthedrugis
observed.
Forexample,10%W/Vcalciumgluconateininjectionisa
supersaturatedsolution.Butinordertoreducetheriskof
crystallization,theI.P.suggeststheuseofcalciumsaccharate(More
solublecalciumsalt)asastabilizer.Apartofcalciumgluconate(not
morethan5%)isreplacedbycalciumsaccharate.

6. .
Suspensions –
particlesslowlybecomebiggerinsizeandfinallymayformahard
cake.Thesecrystals,ifpresentintheinjection,mayblockthe
hypodermicneedle.Theseparticlesproducegrittytexturewhen
appliedasanophthalmicpreparation.
Preventive measures include :-
Selectsuitablestorageconditionstoreducefluctuationsinambient
temperature.
Increasetheviscosityoftheproductsothatdiffusionofsolute
moleculesontothecrystalsurfacewillbehindered.
Include surface active agents in formulations. These agents get
adsorbed on the surface of the crystal and inhibit the further
deposition of solute molecules.

7. Polymorphism :-
Polymorphs exhibitsignificantdifferencesinimportant
physicochemicalpropertiessuchassolubility,dissolutionrateand
meltingpont.
Ingeneral,moresolublemetastabledrugisemployedinthe
manufacture.
Forexample,cortisoneacetate,formIIismoresoluble(metastable)
andformulatedasanaqueoussuspension.Duringstorage,itmaybe
convertedintoformIV(morestableform).Suchchangesleadto
cakingofthecortisoneacetatesuspension.
Normally suspending agents such as methyl cellulose are added to
prevent the conversion owing to enhanced viscosity and limited
diffusion of molecules.

8. .
Colourchanges :-
Colourchangesindicatesomekindofchemicalorphotochemical
decompositionoftheactiveingredients,dyesorotheringredients.
Colour-fadingofdyesisafairlycommontypeofinstability.
Indigocarminedyetendstofadeinthepresenceofreducing
substances(lactoseanddextrose).Tartrazinetendstofaderapidlyin
thepresenceofadditives(surfaceactiveagents)orlight.
Colourdevelopment:-aspirintabletsbecomepinkandascorbicacid
tabletsturnyellowishbrown.Adrenalineonexposuretoairbecomes
red.
Preventive measures :-
protecttheproductfromlightandair.
Avoidusingreducingsubstances(dextroseetc.,)asadditives.
IncludeUV-absorbingsubstancessuchas2,4-dihydrobenzophenone
intheformulation.

9. CHEMICAL DECOMPOSITION OF
DRUGS
-PREVENTIVE MEASURES

10. Hydrolysis :-
thegeneralprinciplesthatgovernhydrolysisreactionsare,
Drugswithesterandamidegroupsreactwithonemoleculeofwater
andundergohydrolysis.Estergroupsbreakfasterthanamidegroups.
Drugsareeitherweakacidsorbases,sotheymaybeavailableas
ionicformsorneutralmolecules.Hydrolysisreactionbetweenionic
speciesproceedsfasterthanwithneutralmolecules.
HydrolysisreactionsarecatalysedbyH
+
and(OH)
-
ions.Hydroxylions
catalysehydrolysisbyabout100to1000timesmoreactivelythan
hydrogenions.
Theseprincipleshelpinrationalisingthedesignofformulationsfromstability
pointofview.

11. Examples of drugs decompose by hydrolytic pathway are :-
Esters Amides
Aspirin Chloramphenicol
Procaine Ampicillin
Atropine Cephalosporins
Barbituricacids

12. Drugs that contain ester groups undergo hydrolysis to give acids and
alcohols.
Ex :-procaine undergoes hydrolysis & give P-amino benzoic acid and
diethyl amino ethanol.
For the sterilization of procaine solution, it was suggested that
autoclaving at 120
0
C for shorter period of time is preferred to prolonged
heating at 100
0
C.

13. Amides undergo hydrolysis, though at a slower rate than esters.
Ex :-chloramphenicol decomposition is influenced by acids, bases,
phosphate ions, acidic and citrate buffers.

14. Protection against hydrolysis :-
Hydrolysisreactionsareknowntooccurin
presenceofmoisture,catalyticspeciesH
+
and
(OH
-
).
pretectivemeasuresshouldaimateleminatingthe
influenceofthesefactorsonthedrug.

15. Buffers :-
drugsmaybestabilizedbytheuseofbuffers.
TheP
H
ofthesolutionshouldbeadjustedsothatthedrugwillhave
maximumstabilityandtherapeuticactivity.
Ingeneral,optimalP
H
willbebetween3.5and5,sinceinthatrange
theH
+
and(OH
-
)catalysedhydrolysisareaboutequal.
Example:-
PilocarpineishighlyactiveinalkalineP
H
andhighlyirritatingtothe
eyeandalsodecomposesrapidly.
Therefore,topreventhydrolysis,acidicP
H
hastobeselected.
Selectabufferwithlowbuffercapacitysothatwhenadministeredin
theeye,theP
H
graduallyrisesandreleasesthefreebasefordrug
action.
Forthisreason,boricacidbufferofap
H
5.0withlowbuffercapacity
isselected.

16. Complexation:-
hydrolysisofbenzocaineinaqueoussolutioncanbeinhibitedbythe
additionofcaffeinewhichformsacomplex.
Asaresultofcomplexation,theattackofcatalyticspecieson
benzocainemaybereduced.
Theion-dipoleinteractionsbetween(OH
-
)orH
+
ionsanddrug
moleculeswillbereduced.
nowtherateofhydrolysisdependsontheamountoffree
uncomplexedbenzocainepresentinsolution.
Astheamountofcaffeineincreases,moreandmoreamountof
benzocainewillbecomplexed.Thisleadstodecreasedhydrolysis.
Thus,theselflifeoftheproductcanbeprolonged.
Otherdrugswhichmaybestabilizedbycomplexationareprocaine,
tetracaineetc.

17. Suppression of solubility :-
whenthesolubilityofadrugdecreases,theconcentrationofdrugin
solutionphasewillbedecreased.Hence,therateofhydrolysisis
reduced.Asmostofthedrugisintheinsolublestate,onlyasmall
factionwillbeinsolutionform.Now,theratedependsonthe
saturationsolubilityofthedrugandfollowszeroorderreaction.
i.Additives:-citrates,dextrose,sorbitolandgluconates,when
combinedwithdrugs,thesolubilityofdrugswillbesuppressed,
probablybecauseofdecreasedhydrationofdrugmolecules.
ii.Salts:-thedegradationofpenicillincanbepreventedbyusing
poorlysolublesaltofprocainepenicillininthedosageform.This
preparationresultsinasuspensionandfollowszeroorder.
Ex:-benzathinepenicillinG.
iii.Derivatives:-poorlywatersolublederivativessuchasesters(higher
fattyacids)ofdrugscanbeusedtoreducethetendencyof
hydrolysis.
Ex:-erythromycinpropionate,
erythromycinstearate,
chloramphenicolpalmitateetc.

18. Removal of water :-
asthepresenceofwaterisresponsibleforhydrolysis,itis
bettertoavoiditscontactwiththedruginthepreparation.
Thisisachievedby–
i.Storingthedrugindryform.Whendesired,reconstitutethe
product.
Ex:-streptomycindrypowderforinjection.
ii.Usingwater-immisciblevehicleforthedispersionofdrug.
Ex:-aspirininsiliconefluid.

19. Oxidation :-
Oxiditationinvolvestheremovalofelectronfromamolecule.
Thereactionbetweenthecompoundsandmolecularoxygeniscalled
autooxidation.
Infatsandoils,autooxidationofunsaturatedfattyacidsproceedsin
thepresenceofatmosphericoxygen,lightandtracesofheavymetals
ororganicperoxides.
Ex:-Therateofoxidationofascorbicacidisincreasedbyafactorof
10
5
,whencopperionsarepresentintheconcentrationof0.002M.
similarlyhydroperoxidescontainedinpolyethyleneglycol
suppositorybaseshavebeenimplicatedintheoxidationofcodeineto
codeine-N-oxide.

20. The general principles that govern an oxidation
reaction are :-
i.Thepresenceofatmosphericoxygen(alsoair)promotestherateof
oxidation.
ii.Sinceoxidationfrequentlyinvolvesfreeradicals,chainreactions
occur.Lightprovidesthenecessaryenergytoinitiatetheoxidation
process.
iii.Thepresenceoftracemetalsalsoacceleratetherateofoxidation.
iv.Organicperoxidespromotethechaininitiationandpropagatethe
oxidationreaction.
v.Drugsareeitherweakacidsorbases.Therefore,thesemaybe
availableasionicformsorneutralmolecules.Oxidationreaction
betweenionicspeciesproceedsfasterthanwithneutralmolecules
(toalargeextentitissolubilityrelatedphenomenon).
vi.OxidationreactionsarecatalysedbyH
+
andOH
-
ions.Hydroxylions
catalyseoxidationfasterthanhydrogenions.Alkalinesolutionsare
knowntoreactwithatmosphericoxygenandformsoxides.

21. Drugs which decompose by oxidation pathways are :-
Arachiloil Vitamin A
Ethyl oleate Riboflavin
Cloveoil Vitamin B
12
Cinnamon oil Ascorbic acid
Promethazine Morphine
Epinephrine prednisolone

22. The autooxidation kinetics of ascorbic acid has been
extensively studied.
The overall reaction may be represented as :-

23. Influence of trace metals :-
the scheme of oxidation of ascorbic acid by cupric ion is as follows :
Ascorbate ion in solution slow oxidation, Cu
2+semiquinone
rapid oxidation, O
2 dehydro ascorbic acid
Whensolutionsarefreefromtracesofcopper,ascorbicacidisnot
oxidizedbymolecularoxygentoameasurableextent,exceptin
alkalinesolutions.
However,eventracesofcopperleadtotherapidoxidationof
ascorbicacid.
WhenCOandKCNareaddedtotheabovereactionmixture,they
formcomplexeswithmetalions,andtherefore,oxidationofascorbic
acidisinhibited.
Thesereactionsdemonstratetheinfluenceofcupriciononthe
oxidationofascorbicacid.

24. Influence of air on oxidation :-
Therateofdecompositiondecreaseswhenhigher
concentrationofascorbicacidisused.
Itispresumedthatapartoftheascorbicacidreactswith
oxygenandthusdepletesfreeoxygen.
Whenairisbubbledthroughthereactionmixture,therateof
oxidationisenhanced.
Whendissolvedoxygenismaintainedatsaturationlevel,the
reactionrateremainsconstant.
Therefore,oxygenisresponsiblefortheautooxidation
reactions.

25. Influence of ionic species of drugs :-
Ascorbic acid can exists as a singly charged or doubly
charged ion.
In the absence of copper ions, oxygen is found to react with
divalent ions at about 10
5
times faster compared to its reaction
with monovalent ascorbate ion.
When copper ions are added, oxidation of singly charged
ascorbate ion alone is found to be catalysed.

26. Influence of acidic and basic ion species :-
Theacidandbasecatalysedoxidationonascorbicacid
proceedsasfollows.Dehydroascorbicacid(degradation
product)furtherdegradestogiveketogulonicacid,which
inturngivesthreonicacidandoxalicacid.
Ascorbic acid H, (OH) dehydro ascorbic acid
ketogulonic acid Threonic acid + oxalic acid
Ingeneral,autooxidationproceedsmorereadilyinalkaline
mediumthaninacidicsolution.
Alkalinesolutionsareknowntoreactwithatmosphericoxygenand
formoxides.

27. Protection against oxidation :-
Oxidationreactionsareknowntooccurinpresence
ofoxygen,tracemetals,H
+
and(OH
-
)ions.
Protectivemeasuresshouldaimateliminatingthe
influenceofthesefactorsonthedrug.

28. Antioxidants :-
Tocopherolsarethenaturallyoccurringantioxidants.
Otherex:-
butylatedhydroxylanisole(BHA),
butylatedhydroxyltoluene(BHT),
propylgallateetc,
Thesearewidelyusedinfoods,cosmeticsanddrugs.
Theseagentsareactbybreakingthefreeradicalchainreactions
atthestepofchainpropagation.
Mostofthesecompoundsareoil-solubleantioxidants.
Watersolubleantioxidantsactbypreferentiallyundergoing
oxidationinsteadofthedrugitself.
Ex:-ascorbicacid.
Compounds having–SHgroupsconsumemolecularoxygen
presentinsolution.
Ex:-cysteine,acetylcysteine,thioglycolicacidetc.

29. Chelating agents :-
Additionofachelatingagenttoaproductwillbeusefulwhentraces
ofheavymetalscatalysetheoxidation.
SubstancessuchasEDTA(ethylenediaminetetraaceticacid)citric
acidandtartaricacidformcomplexeswithheavymetals.
Thus,metalionsarenotavailabletocatalysetheoxidation.
ex:-additionofEDTAtothebuffersystempreventsthedegradation
ofdrugssuchasprednisoloneandascorbicacid.
Anothervariationisthatboricacidformsaonetoonechelate
directlywiththedrug,epinephrine.
Thechelatedepinephrineisfarlesssusceptibletosulfiteattack
thanfreeepinephrine.
Thusoxidationofepinephrineisinhibited.

30. Vehicles :-
usuallywaterisusedasasolventformostproducts.
Thereplacementofwaterbyothersolventswhenusedin
combinationwithwater,theyhavecatalyzingeffecton
oxidation.
Productionofhydroperoxidesthroughthesesolventsis
implicatedinthedegradation.
Severalphysicochemicalpropertiesofsolventssuchas
internalpressure,solubilityparameter,dielectricconstantand
ionicstrengtharecorrelatedfortheratesofareaction.

31. .
•Micellarsolubilisation:-
surfactantssuchaspolysorbate80enhancetherateofoxidation
ofascorbicacidatlowconcentration,butprotectaboveits
criticalmicelleconcentration(CMC),presumablybyentrapping
thedrugsinthesphericalmicelles.
Sometimes,sphericalmicellesofferasiteforsurfaceadsorption
ofcatalyticionsandenhancerateofreaction.
Buffers:-
buffersystemimpartsstabilitywhenoxidationiscatalysedbyH
+
or(OH
-
)ions.
ChooseabufferwithappropriateP
H
tomaintainmaximumstability
oftheproduct.

32. Environmental control measures :-
Oneormoreofthepreventivemeasuresareemployedtostabilize
theproductfromoxidation.
i.Preventtheexposuretolight:-lightisresponsiblefor
oxidation.Thepreparationisprotectedfromthelightby
employingambercolouredbottlesorusingappropriate
packagingbmaterial (cardboard).
Ex:-morphinesulphateinjectionUSPisprotectedfromlightby
usingambercolouredampoules.
ii.Oxygenfreeenvironment:-oxygenenhancesoxidative
degradation.Therefore,airisreplacedwithinertgasessuchas
nitrogenorcarbondioxide.Similarly,useofoxygenfreesolvents
inmanufactureisadvisable.
iii.Lowtemperature:-sincehightemperatureenhancestherate
ofreaction,theproductisstoredinacoolplace.

33. Miscellaneous reactions
preventive measures

34. Isomerism :-
somedrugsoftenhavesomestructuralformula,butpossessdifferent
stereochemicalformintoanotherleadstoinactiveorlessactive
drugs.
Opticalisomerisation:-
insolutions,theopticallyactiveformofadruggetsconvertedintoits
enantiomorph.
Thisprocesscontinuesuntilthetwoformsareequalinconcentration.
Theopticalactivityatequilibriumwillbezero,i.e.,opticallyinactive.
Ingeneral,recemisationreactionsundergodegradationin
accordancewithfirstorderkinetics.
Ex:-(-)Adrenaline (+/-)Adrenaline
greaterbiologicalactivity (+and–is50:50)lesspotent
Preventivemeasures:-theproductisprotectedfromlightandheat.
OptimumP
H
hastobemaintainedformaximumactivity.

35. .
Epimerization:-Inthiscase,thecompoundhasmorethanone
asymmetriccarbonatoms.Whileoneasymmetricatomremainsstatic,
theothercarbonrotatestogiveanepimer.Atequilibrium,both
epimersarepresent,butneednottobeinequalproportion.Inother
words,thesolutionmaystillexhibitopticalactivity.
Ex:-ergometrine ergometrinine
insolution lessactive
Geometricisomerisation:-inthiscase,thecompoundsexistsastrans
andcisisomers,basedontheirrelativespatialconfigurationof
groupsaroundadoublebond(s).Thesechangesmaybringabouta
correspondingchangesinitsbiologicalactivity.
Ex:-vitaminApalmitate 6-momo-cisderivative+2,6-di-cisderivative
moreacitve lessactive

36. .
Polymerization:-Thesetypesofreactionsarenotoftentheinitialcauseof
drugdecomposition.Primarydecompositionproductsmayreactfurther
andpolymerise.
Ex :-dextrose injection autoclaving 5-hydroxymethyl furfural
polymerise straw colouredsolution
Absorptionofcarbondioxide:-solutionsabsorbcarbondioxidefromthe
atmosphere.
Ex :-sodium hexobarbitoneiv injection salt hydrolysis solution basic P
H
absorb CO
2 acidic P
H
hexobarbitoneprecipitate
Preventivemeasures:-theproductisstoredinwell-filledandwell-closed
containers.Manufacturerssupplytheproductasadrysterilepowder.The
instructionshouldbetodissolvethedrugbeforeuseincarbondioxidefree
sterilewaterforinjection.

37. .
Decarboxylation:-Thesetypeofreactionsarenormallyobservedwhena
parentralsolutioncontainssodiumcarbonate.Duringautoclaving,the
carboxylicacidgroupswillbekockedoff.
Ex :-sodium p-aminosalicylicacid (PAS, Anti-TB drug),
procaine hydrochloride (local anesthetic)
Procain(clear solution) hydrolysis p-amino benzoic acid
-CO
2 aniline liquid light drakcolouredliquid
Preventivemeasures:-carbondioxidegasispassedintothesolution
foroneminute.Thecontainerissealedsoastobeair-tigghtpriorto
autoclaving.