week10.1.stability 2004.ppt

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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photodegradationlight energy provides energy ofactivationreaction rate is independent of T

photo-oxidation catalyzed by light nifedipine, colchicine,

chlorpromazine, riboflavin


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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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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?

week10.1.stability 2004.ppt

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