CHEE 440 1

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
chemical
physical
microbiologic
therapeutic
toxicologic
CHEE 440 2
Degradation Mechanisms
Hydrolysis
cleavage of bonds by action of water
esters
procaine, atropine, aspirin
amides
chloramphenicol, penicillin,
cephalosporins
CHEE 440 3
Degradation Mechanisms
Oxidation
molecule gains O or loses H
susceptible compounds
phenols, aromatic amines,
aldehydes, ethers, unsaturated
aliphatic compounds
examples
epinephrine, vitamin A, ascorbic
acid

CHEE 440 4
Degradation Mechanisms
photodegradation
light energy provides energy of
activation
reaction rate is independent of T
photo-oxidation
catalyzed by light
nifedipine, colchicine,
chlorpromazine, riboflavin
CHEE 440 5
Degradation Mechanisms
isomerisation
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
CHEE 440 6
Degradation Mechanisms
Interactions between formulation
compounds
buffers
general acid-base catalysts
formation of amides
benzocaine and citric acid

accelerated photodecomposition
riboflavin in presence of nonionic or
anionic surfactant
CHEE 440 7
KINETICS
rates and orders of reactions
use
more stable dosage forms
storage conditions
prediction of shelf life
factors
concentration
temperature
light
catalysts
CHEE 440 8
Factors governing
stability
Liquids
pH
temperature
ionic strength
solvent
oxygen
Solids
excipients
CHEE 440 9
EFFECT OF PH
Catalyst
substance that influences rate of
reaction but is not changed chemically
either accelerates or inhibits
does not change position of equilibrium
no change in AG
o

form a complex with reactant
decomposes to form product + catalyst
CHEE 440 10
Acid-Base Catalysis
accelerated decomposition in
presence of acid or base
often buffered therefore catalyzed

specific acid-base catalysis
rate law contains [H
3
O
+
] or [OH
-
]
CHEE 440 11
Hydrolysis of Ester
in acidic solution
ester = S
water = W
product = P
S+H
+
SH
+
SH
+
+ W
k
P
dP
dt
= k
obs
S | |
k
obs
= k
1
H
+
| |
CHEE 440 12

Hydrolysis of Ester
base-catalyzed degradation
S+OH

k
2
P
dP
dt
= k
obs
S | |
k
obs
= k
2
OH

| |
CHEE 440 13
Example
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 k
2
for this reaction.
CHEE 440 14
Solvent catalysis
indicated by minimum region of k
versus pH plot
can occur along with both acid and
base catalyzed degradation

dP
dt
= k
o
+ k
1
H
+
| |
+ k
2
OH

| | ( )
S | |
l
o
g

k
o
b
s

pH
CHEE 440 15
General Acid-Base
Catalysis
catalysis in buffered solution by
other than H
+
or OH
-

k
obs
vs pH diagram deviates from
expected behavior
streptozotocin in phosphate buffer
CHEE 440 16
Effect of T
any change in conditions produces
different k
Arrhenius



A = Arrhenius factor
frequency of collisions
E
a
= activation energy
minimum energy required per
collision
used in accelerated stability testing
k Aexp
E
a
RT
CHEE 440 17
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 18
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 19
Effect of Ionic Strength
ionic strength,



influences rate constant
=
1
2
m
i
z
i
2

logk = logk
o
+ 2Az
A
z
B

CHEE 440 20
Solid Dosage Forms
Stability concerns
moisture
hygroscopic excipients
excipient catalyzed reactions
ex. Mg stearate lubricant
CHEE 440 21
Drug Stabilization
primarily hydrolysis
strategies
optimum pH, buffer, solvent
refrigeration
complexation agent
dosage form
micelles, suspensions
oxidation
antioxidants
undergo oxidation faster
sodium bisulfite, ascorbic acid
ascorbyl palmitate, butylated
hydroxytoluene (BHT), vitamin E

CHEE 440 22
Shelf-Life
effective period of storage and
use
t
90

time required to degrade 10% of
the drug
90% drug still active
determined by reaction kinetics

CHEE 440 23
t
90

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
CHEE 440 24
Example
An ophthalmic solution has a
mydriatic drug present at a 5 mg/ml
concentration. The drug degrades by
first order kinetics (k
1
= 0.0005/day).
how long will it take for the drug to
degrade to 90% of its original
concentration?