STABILITY

Ideally any commercial pharmaceutical product should have a

shelf life of 5 yrs and should not fall below 90-95% potency under
recommended storage.
In designing a solid dosage form it is necessary to know the
inherent stability of the drug substance, excipients to be used,
formulation procedure.
For a drug substance, we need to study 3 categories of stabilities1. Solid state stability of drug only
2. Compatibility studies ( drug+ excipients )
3. Solution phase stability

1. SOLID STATE STABILITY

It includes both physical and chemical stability
Physical changes caused by Polymorphic transitions and
Hygroscopicity.
Chemical changes such as solvolysis, oxidation, photolysis,
pyrolysis.
Examination of the chemical structure.
Example- presence of unsaturation makes the compound
susceptible to free radical mediated or photocatalyzed oxidation.
Strained rings are more prone to pyrolysis.

PHYSICAL CHANGES/INSTABILITY
Solubility
pKa
Melting point
Crystal form
Equilibrium moisture content.
Example- amorphous materials are less stable than their
crystalline counterparts.
A relatively dense material may better withstand ambient
stresses aminobenzylpenicillin trihydrate is more denser and
stable than its amorphous form.

CHEMICAL CHANGES/INSTABILITY
Solid state reactions are generally slow and it is customary to use
stress conditions in investigation of stability.
Data obtained under stress is then extrapolated to make
prediction of stability.
High temperature can drive moisture out of a sample and render
the material apparently stable otherwise prone to hydrolysis.
Example- Above 65% relative humidity the beta form of
chlortetracycline hydrochloride transforms into alpha form.
Rate of Reaction
Expressing speed of a reaction:
as the decrease in concentration of any reacting substance
as the increase in concentration of the product per unit time.

dC
C n
dt

If C is the concentration, then the rate of reaction:

where n=0,1 or 2 for zero, first & second order reactions respectively

Order of Reaction
Manner in which the rate of reaction varies with the concentration of the
reactants
Most processes involving ADME can be treated as first- order processes

 Some drug degradation processes can be treated as either First or zero

order processes
Some drug substances obey Michaelis-Menten kinetic process

First Order Kinetics

dC
kC
dt

n=1 and the reaction rate is dependent on the concentration of

one of the reactants in the formulation.

C is the concentration remaining un-decomposed, unabsorbed, yet to be

distributed, metabolized or excreted at time t as the case may be
k is the first order rate constant.

On integration, the equation above gives:

ln C ln Co k t 0

log C log Co

kt
2.303

On rearrangement and conversion to log in base 10:

Zero order reaction

In this type of reaction, n=o and the reaction rate is independent of the
concentration of the reacting substance.
The rate of change is constant.
Here, factors other than concentration of reactants constitute the limiting
factor e.g. solubility or absorption of light (photochemical reactions).
When solubility is the limiting factor, only the proportion of drug in solution
undergoes degradation:
As the drug is consumed in the degradative reaction, more drug
goes into solution until all solid (C) has reacted.
Until this has happened, the degradation process will not be
dependent on the total conc. of drug but on the proportion in
solution, thereby producing a zero order process.

dCo
k
dt

Zero order Equation:

Co= original concentration of reacting material, k=reaction rate constant,

dt= change in time.

Ct Co kt

Expression of zero order equation:

Ct=conc. at time t, Co=conc. at time o.

Plot of C against t gives a straight line with slope of -k o

INI PPT YANG HALAMAN 37

TUTORIAL QUESTION
1. An ophthalmic solution has a shelf life of 6 hours at room temperature (25
C). Calculate the estimated shelf-life in a refrigerator (5 C)
2. An antibiotic has a shelf life of 48 hours in the refrigerator (5 C). What is
its estimated shelf-life at room temperature (25 C)?
3. In what ways can chemical instability be manifested on formulated
products? List and discuss four main types of reactions involved in
chemical degradation.
4. A drug suspension (125 mg/ml) decays by zero-order kinetics with a
reaction rate constant of 0.5 mg/ml/hr. What is the concentration of intact
drug remaining after 3 days?
5. How long will it take for the suspension in question 4 above to reach 90 %
of its original concentration?
6. An ophthalmic solution of a mydriatic drug present at 5 mg/ml
concentration exhibits first order degradation with a rate of 0.0005/day.
How much drug will remain after 120 days? How long will it take for the
drug to degrade to 90 % of its original concentration?
7. The rate constant for decomposition of 5-hydroxymethylfurfural was 1.173
H-1 at 120 C and 4.860 H-1 at 140 C. What is the activation energy and
frequency factor, A in sec-1 for the breakdown of 5HMF in this temperature
range?
8. Analysis of the rate of degradation of a colourant in a multi-sulfa drug
preparation shows the following results:

K/sec
a. Assuming a first-order process, compute the
C
activation energy and the value of K at 25 C
4
0

0.000
11

5
0

0.000
28

YANG AKU COPY DISINI IALAH BENTUK GAMBAR DI MS WORD

YANG SEDANG KAMU KERJAIN, BIAR KAMU MUDAH KERJAINNYA,

6
0

0.000
82

SEMANGAT INGEEE

7
0

0.001
96

DEAR INGE,