General considerations and

concept of kinetics and drug

stability

Ms. Nur Najihah ‘Izzati Mat Rani

CONTENTS:
Lesson Learning
Outcome
Upon completion of this lesson
students will be able to understand

• Order of Reaction
• Method of determining reaction
order
• Factors affecting the rate of
chemical reaction
• Kinetics of chemical decomposition
• Stability studies and expiration date
STABILITY STUDIES AND EXPIRATION DATE
ARRHENIUS EQUATION :

It explains the effect of temperature on rate of a reaction.

According to Arrhenius, for every 10º rise in temperature, the speed of
reaction increases about 2-3 times.

k = A e -Ea / RT OR

k = Chemical reaction rate

A = Pre-exponential factr
Ea = Activation energy
R = Gas constant
T = Temperature in Kelvin

Arrhenius factor is the frequency of molecular collisions occurring between the molecules.
Log k = log A – Ea / 2.303 RT
Disadvantages of Arrhenius equation:

• At higher temperature evaporation of solvent takes place and thus changes in

concentration.
• At higher temperature change in solubility and humidity (decreases) which cannot be
correlated with room temperature.
• For disperse systems at higher temperature viscosity decreases which can change
physical characteristics resulting in potentially large errors in prediction of stability.
• Different degradation mechanisms may predominate at different temperatures thus
making stability prediction difficult.

5
STABILITY STUDIES AND EXPIRATION DATE
Estimation of energy of activation: *** Sloped-apa explain all of that

Activation energy is the minimum energy that a molecule should possess so that the molecular
collisions produce the product.

A graph can be drawn by taking log k on y-axis and reciprocal temperature (1/T) on x-axis.

A straight line is obtained, the slope of the line is negative and the magnitude is Ea / 2.303 R.

The intercept corresponds to log A

All the constants in the Arrhenius equation can be obtained from the graph.
 STABILITY
STUDIES AND
EXPIRATION
DATE
STABILITY STUDIES AND
EXPIRATION DATE

Steps involved in prediction of shelf life:

• Liquid samples of preparation were stored at different

temperatures like 40,50,60,70,85,100 & 1210c at respective
RH.1 sample each should be kept at incubator
temperature, 300C at 70% RH, 370C at defined RH.
• Samples are withdrawn at different intervals of time (3
months for 1 year and 6 months for 2 year) and determine
the concentrations.
• From this take a graph by taking absorbance or
concentration drug remaining on y-axis and time on x-axis.
 STABILITY
STUDIES AND Absorbance
EXPIRATION
DATE

Time (hours)
STABILITY STUDIES AND EXPIRATION DATE

By applying Arrhenius equation graph is drawn taking log k values

on y-axis and reciprocal of absolute temperature is taking on x-axis.

From this linear plot we can extrapolate the plot to room

temperature 250c.

With the k value is obtained, then substituting the k value the shelf
life can be obtained.
STABILITY STUDIES AND EXPIRATION DATE

800c t90% or t0.9 : 𝒕𝟎.𝟗 =

𝟐.𝟑𝟎𝟑
𝒍𝒐𝒈
𝑪𝟎
𝒌𝟏 𝟎.𝟗𝑪𝟎
700c
600c t0.9 = 0.11/ Cok2
500c
Log k 400c
300c
250c
200c

1/T
STABILITY STUDIES AND
EXPIRATION DATE

• Another method to know the shelf life.

• Here we are taking the parameters like log
percent of drug remaining versus time in
days.
• Here we know the time for 90% of drug
decomposed in how many days.
STABILITY STUDIES AND
EXPIRATION DATE

• By plotting the graph between log

time to 90% and time.
• Then we get a straight line there
by we can extrapolate the line to
room temperature so that we can
get the shelf life.
STABILITY STUDIES AND EXPIRATION DATE

Limitations:

• Limited to temperature.
• Result applied to 1 set of preparation cannot applied to other preparation.
• Stability studies based on T is of NO USE if the degradation is due to other
reasons.(Microbial, diffusion or physical).
• Prediction become erroneous of the ORDER changes on HIGHER T.
• Prediction become erroneous of the order changes on when prep. studied.
STABILITY STUDIES AND
EXPIRATION DATE
Overages:

• It is the excess quantity of drug to be added in a

preparation to maintain 100% of drug in the
formulation as per label claim.
• It can be known from shelf life.
• Overages added to the formulation within the limits
• But for highly potent drugs overages should not be
used
• For vitamins it is essential to use overages because
vitamins degrade at room temperature.
STABILITY STUDIES
AND EXPIRATION
DATE

Advantages:

• Stability of a product can be estimated.

• Shelf life and expiry date can be known.
• Storage conditions can be known.
 STABILITY STUDIES
AND EXPIRATION DATE

Guidelines for stability testing:

• ICH: international conference on

harmonization
• WHO: world health organization.
• FDA: food and drug administration.
• Globally every pharmaceutical companies
should follow these guideline.
STABILITY STUDIES AND EXPIRATION DATE

ZONE 1 Great Britain , North Europe, Russia, Canada.

ZONE 2 US, Japan, South Europe.

ZONE 3 Iran, Iraq, Sudan.

ZONE 4 Brazil, Ghana, Indonesia, Philippines. Malaysia

.
STABILITY STUDIES AND EXPIRATION DATE g
Zones Condition Temperature Relative humidity

Zone 1 Temperate 20oc 42

Zone 2 Sub tropical 22oc 52

Zone3 Hot/dry 27.9oc 35

Zone4 Hot/humid 27.4oc 76

STABILITY STUDIES AND EXPIRATION DATE

STUDY STORAGE CONDITION MINIMUM TIME PERIOD

COVERED BY DATA AT
SUBMISSION
Long Term 25º C ± 2º C 12 months
(Ambient) 60%RH ± 5%

Intermediate 30º C ± 2º C 6 months

(controlled 60%RH ± 5%

Accelerated 40º C ± 2º C 6 months

75%RH ± 5%
STABILITY STUDIES AND
EXPIRATION DATE
• Storage condition for accelerated testing
according to ICH and WHO is 40 o C ± 2 oC RH
75%±5%.

• If the product is unstable in the above conditions

intermediate conditions are used 30 oC±2 oC RH
60%±5%.

• FDA prescribes 0,2,4 and 6 months.

• WHO prescribes 0,1,2,3 and 6 months.
• ICH prescribes 3 months in 1 year and frequency
of 6 months in 2 year and then annually.
 how to determine
know

Hear

E
recording
&

-
stability
calculation

degration -
what kind
why
ways
?
of

to overcome
STORAGE
CONDITION
• Cold condition : 2-80C
• Cool condition: 8-250C
• Room temperature: working
temperature ≈ 250C
• Warm temperature: 30-400C
• Excessive heat: above 400C
• Controlled temperature: 20-250C
• Freezing condition: upto -200C
References

• Attwood, D. (2012). Physical pharmacy (2nd ed.) Pharmaceutical press.

• Sinko, p.J. (2011) Martin's pHysical Pharmacy And Pharmaceutical Sciences : Physical
Chemical And Biopharmaceutical Principles In The Pharmaceutical Sciences (6th ed.).
Lippincot williams and wilkins.