Accelerated stability studies Shelf life determination , Limitations and Interpretation

1. JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY KAKINADA.
Presented To
K.Srinivas Reddy Sir
Presented By
V.Mounika
M.Pharm; Pharmaceutics
18IS1S0315
ACCELERATED STABILITY
STUDIES

2. ACCELERATED STABILITY STUDIES
 Stability of a pharmaceutical preparation is the capability of a
formulation in a specific container closure system to remain within
its physical , chemical , microbiological, therapeutic and
toxicological specifications throught its life.
 Shelf life: time taken for drug to decrease to 90% of initial
concentration.
FACTORS AFFECTING SHELF LIFE OF DRUGS
1. Moisture, hydrolysis and pH
2. Oxygen
3. Light
4. Temperature
5. Microbes
6. APIs and excepients
7. Physiological properties like hygroscopic nature, crystalline or
amorphous nature.

3.  Shelf life of drug can be determined by two methods
1. Accelerated stability studies
2. Real time testing method
Accelerated stability studies
 All medicinal products decompose with time. Instability in modern
formulations is often detectable only after considerable storage
periods under normal conditions.
 To assess the stability of a formulated product it is usual to expose
it to “high stress”, i.e. condition of temperature, humidity and light
intensity that cause break down.
 High stress conditions enhance the deterioration of the product and
so reduce the time required for testing.
 Thus these are the studies designed to increase the rate of chemical
degradation and physical change of a drug by using exaggerated
storage conditions as part of the formal stability testing
programme.

4. Objective
Main aim of accelerated stability study to predict the stability profile
of a drug product that prediction of shelf life of the product before
launching into market.
The rapid detection of deterioration different initial formulations of the
same product. This is of use in selecting the best formulation from a
series of possible choices.
Significant change occurs due to accelerated testing
Physical Changes under Accelerated conditions of Temperature &
Humidity
Under Light, both Primary and Secondary packaging affected, and
fading of container color, and the print is fading.
Effervescent Tablet : Gain of moisture, loss of integrity
Capsule: Color fading in Blister and Sticking in a Glass bottle.

5. Powder : Spread within strip pockets
Suppositories : Softening
Gel :Change in Viscosity of a Gel, Jelly, Cream & Ointment
Lozenges : melting
Emulsions : Phase separation
Stability Profiles: Accelerated stability study

6. Prediction of shelf life from accelerated stability data
1. Garret and Carper method
2. Free and Blythe method
Shelf Life Determination Based on Arrhenius Plot (Garret and
Carper method)
The mathematical prediction of shelf life is based on the application
of the arrhenious equation, which indicates the effect of temperature
on the rate constant, k, of a chemical reaction of thermodynamic
temperature, 1/T, is a straight line.
If the slope of this line is determined from the results of temperature
by extrapolation, the k value obtained. And this k value is substituted
in appropriate order of reaction allows the amount of decomposition
after a given time.

7. Preliminary experiments are there for necessary to determine
this order. methods to determine order of reaction
1. substitution method
2. initial rate method
3. data plotting method
4. half-life determination method
K=Ae-Ea/RT
Log K=Log A - Ea/2.303*RT
Where, K= rate constant
R= gas constant =8.314J/MOL-K
T = absolute temperature
A = frequency factor
Ea = energy of activation

8. Garret and Carper method
1. Keep several samples of the drug product at atleast three
temperatures, such as 40 ⁰C, 50 ⁰C and 60⁰C.
2. Determine the drug content at all three storage points by taking a
number of samples and take the mean drug content. We do this
for a few weeks.
3. At each temperature we plot a graph between time and log
percent drug remaining. If the decomposition is first order this
gives a straight line. If it is zero order, percent drug remaining
versus time will give a straight line.
4. Next we take the log K or log of reaction constant on Y axis and
1/T on X axis and draw a best fit line. This line is the Arrhenius
Plot, extrapolate this line to get k at 25 ⁰C and from this we
calculate the shelf-life.
5. If the reaction is following zero-order
6. Expiration date at 25 ⁰C = Initial potency – minimum potency /
reaction rate at 25 °C
tx =Yo - Yx/ Ko

9. If the reaction is following first order
Expiration date at 25 ⁰C (tx) = Log initial potency – log minimum
potency/reaction rate at 25
tx =log Yo – log Yx / K1
Where Yo = initial potency
Yx = final potency
Ko = zero order constant , K1 = first order constant

10. SHELF LIFE DETERMINATION Based on t90 values (Free
and Blythe /method)
1. Used for liquid products
2. Plot log concentration remaining vs time at 40, 50, 60,
70degree temperature.
3. From curve calculate time required for 90% remaining at
different temperature.
4. Plot t90% v/s absolute temperature
5. From straight Line, find
t90% at room temperature.

11. Limitation of accelerated stability studies
1. Accelerated stability studies are valid only when the breakdown
depends on temperature. Accelerated stability studies are valid only
the energy of activation is about 10 to 30 kcal / mol.
2. In solution phase most reaction has heat of activation in the range of
10 to 30 k.cal / mole. if energy of activation is less than 10 kcal / Mol
its rate would be fast at room temperature .in such cases elevated
temperature has little influence on the decomposition .if energy of
activation is higher than 30 kcal / Mol very high temperature are
required to enhance the degradation. The result obtained for one set of
condition for a preparation cannot be applied to other preparation of
same drug.
3. Stability prediction at elevated temperature is of little use when
degradation is due to diffusion, microbial contamination, and photo-
chemical reaction.

12. INTERPRETATION OF KINETIC DATA
KINETICS: it is the study of the rate at which processes occur.
ORDER OF REACTION This is the number of concentration terms that
determine the rate.
Consider the reaction: A + B → C + D
The rate of the reaction is proportional to the concentration of A to
the power of x, [A]x and also the rate may be proportional to the
concentration of B to the power of y, [B]y. The overall equation is, Rate = k
[A]x [B]y.
ZERO ORDER REACTION
When the reaction rate is independent of concentration of the
reacting substance, it depends on the zero power of the reactant and therefore
is zero order reaction.
In this type of reaction, the limiting factor is something other than
concentration, for example, solubility or absorption of light in certain
photochemical reactions.

13.  The rate of decomposition can be described mathematically as:
Rate of concentration decrease =

 Integrating the equation yields X= Kt + constant
……………… (2)
 A plot of X v/s Time results in straight line with slope equal to K.
 The unit of K is mole L-1 s-1.Half-life is given by equation t1/2=C
/2k

14. FIRST ORDER REACTION
1. When the reaction rate depends on the first power
of concentration of a single reactant, it is considered
to be first order.
2. Examples are Absorption, distribution, elimination
rates. Microbial death kinetics. Thus the rate of
reaction is directly proportional to the concentration
of reacting substance and can be expressed as
follows:
3. Rate of concentration decrease =
4. If concentration of reactant X is ‘a’ at beginning of
reaction when t = 0, & if amount that has reacted
after time t is denoted by x then amount of X
remaining at time t will be (a-x).

15.  Therefore equation (3) can be rewritten as:
 If first order law is obeyed then a graph of log (a-
x) v/s time t will give straight line with slope of –
K/2.303 and an intercept of log a at t = 0.

16.  If first order law is obeyed then a graph of log (a-x) v/s
time t will give straight line with slope of – K/2.303 and
an intercept of log a at t = 0.
Unit of K for first order is time-1 i.e. SI unit is (sec)-1
because K is inversely proportional to t.

17. SECOND ORDER REACTION
Rate of change in conc. of product and reactant is dependent on
second power of conc. of single reactant or to first powers of the
conc. of two reactants.

20. PSEUDO-ZERO ORDER REACTION
In solid state, may drug decomposes by pseudo zero
order i.e. reaction between drug and moisture in solid dosage
form. The system behaves like suspensions and because of
the presence of excess solid drug; the first order rate actually
becomes pseudo zero order
PSEUDO-FIRST ORDER REACTION
Here a second order or bimolecular reaction is made
to behave like first order. This is found in the case in which
one reacting material is present in great excess or is
maintained at constant concentration as compared with other
substance.

21. THANK YOU