Transcript week10.1.stability 2004 - John Stephenson

Stability

the extent to which a product retains,
within specified limits, and throughout
its period of storage and use, the same
properties and characteristics it
possessed when manufactured
 types





CHEE 440
chemical
physical
microbiologic
therapeutic
toxicologic
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Degradation Mechanisms
 Hydrolysis
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
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CHEE 440
cleavage of bonds by action of water
esters
» procaine, atropine, aspirin
amides
» chloramphenicol, penicillin,
cephalosporins
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Degradation Mechanisms
 Oxidation
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CHEE 440
molecule gains O or loses H
susceptible compounds
» phenols, aromatic amines,
aldehydes, ethers, unsaturated
aliphatic compounds
examples
» epinephrine, vitamin A, ascorbic
acid
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Degradation Mechanisms
 photodegradation
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CHEE 440
light energy provides energy of
activation
reaction rate is independent of T
photo-oxidation
» catalyzed by light
» nifedipine, colchicine,
chlorpromazine, riboflavin
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Degradation Mechanisms
 isomerisation
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CHEE 440
conversion of a drug into its optical
isomer
enantiomers often have significantly
different ADME and pharmacological
action
often catalyzed by acid or a base
ex. tetracycline, pilocarpine,
cephalosporin esters
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Degradation Mechanisms
 Interactions
between formulation
compounds

buffers
» general acid-base catalysts
» formation of amides


CHEE 440
benzocaine and citric acid
accelerated photodecomposition
» riboflavin in presence of nonionic or
anionic surfactant
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KINETICS
 rates
and orders of reactions
 use
more stable dosage forms
» storage conditions
 prediction of shelf life

 factors
concentration
 temperature
 light
 catalysts

CHEE 440
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Factors governing
stability
 Liquids
pH
 temperature
 ionic strength
 solvent
 oxygen

 Solids
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CHEE 440
excipients
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EFFECT OF PH
 Catalyst
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CHEE 440
substance that influences rate of
reaction but is not changed chemically
either accelerates or inhibits
does not change position of equilibrium
no change in DGo
form a complex with reactant
decomposes to form product + catalyst
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Acid-Base Catalysis
 accelerated
decomposition in
presence of acid or base
 often buffered therefore catalyzed
 specific
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CHEE 440
acid-base catalysis
rate law contains [H3O+] or [OH-]
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Hydrolysis of Ester
 in



acidic solution
ester = S
water = W
product = P

S  H  SH

k
SH   W P
dP
 k o bsS
dt
 

kobs  k 1 H
CHEE 440
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Hydrolysis of Ester
 base-catalyzed
degradation

k2
S  OH P
dP
 k o bsS
dt


kobs  k 2 OH
CHEE 440

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Example

CHEE 440
Drug X degrades by a base-catalyzed
process in a buffer of pH 9 at room T. If
the initial concentration of X was 0.1 M
and after 4 days there was 0.099 M of X
present, determine k2 for this reaction.
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Solvent catalysis
 indicated
by minimum region of k
versus pH plot
 can occur along with both acid and
base catalyzed degradation

  

log kobs
dP


 k o  k1 H  k 2 OH S
dt
pH
CHEE 440
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General Acid-Base
Catalysis
 catalysis
in buffered solution by
other than H+ or OH kobs vs pH diagram deviates from
expected behavior

CHEE 440
streptozotocin in phosphate buffer
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Effect of T
 any
change in conditions produces
different k

Arrhenius
  Ea  
k  A exp 
 RT  
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CHEE 440
A = Arrhenius factor
» frequency of collisions
Ea = activation energy
» minimum energy required per
collision
used in accelerated stability testing
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Example
 The
rate constant for the
decomposition of expensinin at 120
°C is 1.173 hr-1 and at 140 °C is 4.86
hr-1. Calculate the activation energy
and the Arrhenius factor for this
reaction.
CHEE 440
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Effect of Solvent
 affects
rate constant
polar solvents increase the rate of
reaction where the products are
more polar than the reactants
 nonpolar solvents increase the
rate of reaction where the
products are more nonpolar than
the reactants

CHEE 440
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Effect of Ionic Strength
 ionic
strength, m
1
2
m   miz i
2
 influences
rate constant
logk  logk o  2AzA zB m
CHEE 440
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Solid Dosage Forms
 Stability
concerns
moisture
 hygroscopic excipients
 excipient catalyzed reactions
» ex. Mg stearate lubricant

CHEE 440
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Drug Stabilization

primarily hydrolysis

strategies
» optimum pH, buffer, solvent
» refrigeration
» complexation agent
» dosage form


oxidation

antioxidants
» undergo oxidation faster


CHEE 440
micelles, suspensions
sodium bisulfite, ascorbic acid
ascorbyl palmitate, butylated
hydroxytoluene (BHT), vitamin E
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Shelf-Life
 effective
period of storage and
use
 t90
time required to degrade 10% of
the drug
 90% drug still active
 determined by reaction kinetics

CHEE 440
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t90
 zero-order
t 90
 first
A0 


10k 0
order
 l n 0.9
t 90 
k1
 second
order
1
t 90 
9A 0 k2
CHEE 440
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Example
 An
ophthalmic solution has a
mydriatic drug present at a 5 mg/ml
concentration. The drug degrades by
first order kinetics (k1 = 0.0005/day).
how long will it take for the drug to
degrade to 90% of its original
concentration?
CHEE 440
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