Download - week10.1.stability 2004.ppt
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8/10/2019 week10.1.stability 2004.ppt
1/24HEE 440
Stability
the extent to which a product retains,within specified limits, and throughoutits period of storage and use, the same
properties and characteristics it possessed when manufactured
typeschemical
physicalmicrobiologictherapeutictoxicologic
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Degradation Mechanisms
Hydrolysiscleavage of bonds by action of wateresters
procaine, atropine, aspirinamides
chloramphenicol, penicillin,cephalosporins
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Degradation Mechanisms
photodegradationlight energy provides energy ofactivationreaction rate is independent of T
photo-oxidation catalyzed by light nifedipine, colchicine,
chlorpromazine, riboflavin
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Degradation Mechanisms
isomerisationconversion of a drug into its opticalisomerenantiomers often have significantlydifferent ADME and pharmacologicalactionoften catalyzed by acid or a base
ex. tetracycline, pilocarpine,cephalosporin esters
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Degradation Mechanisms
Interactions between formulationcompounds
buffers general acid-base catalysts formation of amides
benzocaine and citric acid
accelerated photodecomposition riboflavin in presence of nonionic or
anionic surfactant
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Factors governingstability
Liquids pH
temperatureionic strengthsolventoxygen
Solidsexcipients
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EFFECT OF PH
Catalystsubstance that influences rate ofreaction but is not changed chemicallyeither accelerates or inhibitsdoes not change position of equilibriumno change in DGo form a complex with reactantdecomposes to form product + catalyst
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Acid-Base Catalysis
accelerated decomposition in presence of acid or baseoften buffered therefore catalyzed
specific acid-base catalysisrate law contains [H 3O+] or [OH -]
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Hydrolysis of Ester
in acidic solutionester = Swater = W
product = P
S H SH
SH Wk
P
dPdt
k obs S
k obs k 1 H
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Example
Drug X degrades by a base-catalyzed process in a buffer of pH 9 at room T. Ifthe initial concentration of X was 0.1 M
and after 4 days there was 0.099 M of X present, determine k 2 for this reaction.
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Solvent catalysis
indicated by minimum region of kversus pH plotcan occur along with both acid and
base catalyzed degradation
dPdt
k o k 1 H k 2 OH S
l o g
k o
b s
pH
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General Acid-BaseCatalysis
catalysis in buffered solution byother than H + or OH - k
obs vs pH diagram deviates from
expected behaviorstreptozotocin in phosphate buffer
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Effect of T
any change in conditions producesdifferent k
Arrhenius
A = Arrhenius factor frequency of collisions
Ea = activation energy minimum energy required per
collisionused in accelerated stability testing
k Aexp E aRT
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Example
The rate constant for thedecomposition of expensinin at 120C is 1.173 hr -1 and at 140 C is 4.86hr -1. Calculate the activation energyand the Arrhenius factor for thisreaction.
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Effect of Solvent
affects rate constant polar solvents increase the rate of
reaction where the products aremore polar than the reactantsnonpolar solvents increase therate of reaction where the
products are more nonpolar thanthe reactants
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Effect of Ionic Strength
ionic strength, m
influences rate constant
m 12 m iz i
2
log k log k o 2Az A z B m
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Solid Dosage Forms
Stability concernsmoisture
hygroscopic excipientsexcipient catalyzed reactions
ex. Mg stearate lubricant
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Drug Stabilization
primarily hydrolysisstrategies
optimum pH, buffer, solvent
refrigeration complexation agent dosage form
micelles, suspensions
oxidationantioxidants
undergo oxidation fastersodium bisulfite, ascorbic acidascorbyl palmitate, butylatedhydroxytoluene (BHT), vitamin E
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Shelf-Life
effective period of storage anduse
t90 time required to degrade 10% ofthe drug90% drug still activedetermined by reaction kinetics
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t90
zero-order
first order
second order
t 90 ln 0.9 k 1
t 90
A 0 10 k 0
t 90 1
9 A 0 k 2
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Example
An ophthalmic solution has amydriatic drug present at a 5 mg/mlconcentration. The drug degrades byfirst order kinetics (k 1 = 0.0005/day). how long will it take for the drug todegrade to 90% of its originalconcentration?