Contents

Types of Activation
stability
stability testing energy

Shelf life
Stability study Guidelines
prediction

Limitation of
Types of
Climate zone accelerated
study
stability

Current trend
Pharmaceutical Testin
in stability
degradation conditions
g testing
Stability

Stability of pharmaceutical product may be defined as

the capability of a particular formulation in a specific
container/closure system to remain within its physical,
chemical, microbiological, therapeutic and toxicological
. specification.
Stability study

Stability testing/study is termed as a complex

process because of involvement of a variety of
factors including

1 2
stability of the active container/closure system
ingredients used for packaging

3
heat and moisture 5
conditions 4 interaction
encountered type of dosage between active
during shipment, form ingredients and
storage and excipients
handling.
Need for stability study

Provide evidence as
to how the quality
of the drug product
varies with time.

Safety point of view Establish shelf life for

of patient. the drug product.

Determine container Determine

and closure system recommended
suitability. storage conditions
Ultimate achievement

Assurance to Economic Legal

the patient considerations requirement
 THEARAPEUTICAL
STABILITY

CHEMICAL PHYSICAL
STABILITY
STABILITY Stability

MICROBIOLOGICAL TOXICOLOGIC
STABILITY STABILITY
What happens if drug is degraded?

Lowering of concentration/potency

Active to toxic product

appearance

Reduction in
bioavailability
TYPES OF STABILITY TESTING

stability testing

Accelerated stability Retained

Real-Time stability sa
testing
testing mple/ongoing stability
testing
GUIDELINES

ICH

guidelines

WHO FDA
Climate zone
Four climatic zones can be distinguished for the purpose of
worldwide
stability testing, as follows: ICH Stability Zones
Zone Type of Climate

Zone I Temperate zone

Zone II Mediterranean/subtropical zone

Zone III Hot and dry zone

Zone IV Hot humid/tropical zone

Zone IVb ASEAN testing conditions

hot/higher humidity
 Testing Conditions
Long Term/Real-Time stability testing

Climatic Zone Temperature Humidity Minimum

Duration
Zone I 21ºC ± 2ºC 45% RH ± 5% RH 12 Months

Zone II 25ºC ± 2ºC 60% RH ± 5% RH 12 Months

Zone III 30ºC ± 2ºC 35% RH ± 5% RH 12 Months

Zone IV 30ºC ± 2ºC 65% RH ± 5% RH 12 Months

Zone IVb 30ºC ± 2ºC 75% RH ± 5% RH 12 Months

Refrigerated 5ºC ± 3ºC No Humidity 12 Months

Frozen -15ºC ± 5ºC No Humidity 12 Months

Testing Conditions
Accelerated and Intermediate Testing Conditions

Climatic Zone Temperature Humidity Minimum Duration

Accelerate 40ºC ± 2ºC 75% RH ± 5% RH 6 Months

d Ambient

Accelerated 25ºC ± 2ºC 60% RH ± 5% RH 6 Months

Refrigerate
d

Accelerated Frozen 5ºC ± 3ºC No Humidity 6 Months

Intermediate 30ºC ± 2ºC 65% RH ± 5% RH 6 Months

Sampling Frequency

For Long term testing, during first year sampling should be done
every three months, during second year, sampling should be done
every six months and after two years, sampling should be done
once a year.

Accelerated testing should be done at least six months and

it suggests sampling points of 0, 3, 6 months.
Testing parameters of different dosage forms

Tablets Capsules Oral solutions, Topical &

suspensions and Ophthalmic and
emulsions Preparation

Powders and granules for Metered-dose

oral solution or suspension Inhalations and
Nasal
Aerosols
Examples of testing parameters contd

Suppositories Freeze-dried Transdermal Patches

Products

large volume Small volume

parenterals (LVPs) parenterals (SVPs)
ACCELERATED STABILITY TESTING AND ACTIVATION ENERGY

Activation energy is the energy that must be overcome in order for a

chemical reaction to occur. Activation energy may also be defined as the
minimum energy required to start a chemical reaction. The activation
energy of a reaction is usually denoted by Ea.
ARRHENIUS EQUATION

Reaction rates are proportional to the number of collisions per unit time
(of reactant molecules). The number of collisions increases as the
temperature increases. Therefore, the reaction rate increases as the
temperature increases according to Arrhenius equation

K = A e-Ea/RT
logK = logA - (Ea/2.303RT)

K = reaction rate constant

A = frequency factor constant i.e maximum number

of collisions at infinite temperature

Ea = Energy of activation

T = absolute temperature (Kelvin)

Estimation of energy of activation

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 logA

Fig. Arrhenius plot

All the constants in the Arrhenius equation can be obtained from
the graph.
 Estimation of k value

The reaction is conducted at several

temperatures.

Concentration of reactants is determined.

Appropriate graphs are drawn for the kinetic

data.

Arrhenius plot for

Data is processed for all the orders. elevated temperatures

The order of the reaction is identified and

from the slopes of the lines, k values are
calculated for all temperatures.
 SHELF LIFE EXTENSION

To support a shelf life extension, a report must be generated

documenting stability data (for the proposed interval) for three batches
which meet all the following criteria:

No significant
Same Same primary change in the
Same product / manufacturing packaging Same
potency process. material formulation manufacturin
g procedure
Re-stability test after registration

Once the pharmaceutical product has been registered, additional

stability studies are required whenever variations that may affect the
stability of the active pharmaceutical substance or pharmaceutical
product are made, such as major variations like the following:

b. Change in the
a. Change in the composition of the c. Change of the
manufacturing process. pharmaceutical immediate packaging.
product.
PHOTOSTABILITY

Photo degradation may be observed as bleaching or as discoloration of products.

The other effects include cloudy appearance of the product, a loss in viscosity of
formulation, precipitation of active principle, alteration in dissolution rate, Although
many drugs are found to decompose when exposed to light.

Xenon

lamps

By exposing drug substance to 400

& 900 (FC)of illumination for 4 & 2
Artificial
Light Tungsten- weeks to light and another sample
mercury
daylight
Source lamps examined protected from light .
tubes e.g. cycloprofen becomes very
yellow after five days under 900
foot candles of light
Natural
Light
 Limitation of Arrhenius relationship for stability prediction

Stability predictions based on Arrhenius equation are valid only when the break
down depends on temperature

The energy of activation obtained in the study should be between 10 to 30

kcal/mole

When degradation is due to Microbial contamination or Photochemical

reactions

When the product looses its physical integrity at higher temperatures

When the order changes at elevated temperatures

In case of disperse systems, when temperature is elevated viscosity is

decreased and this may introduce errors in the prediction of stability