Definition of Drug Stability
Drug Stability refers to the capacity of a drug substance or
product to remain within established specifications of safety,
identity, strength, quality, and purity in a specified period of
time.
It can also be defined as the study of the extent to which the
properties of a drug substance or a drug product to remain
within specified limits at certain temperature. Properties may
be physical, chemical, microbiological, toxicological or
performance properties such as disintegration or dissolution.
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Definition of Drug Stability……contd
The USP defines the stability of pharmaceutical product as,
“Extent to which a product remains within specified limits
throughout its period of storage (Shelf life) and show the same
properties and characteristics that it possessed at the time of
its manufacturing.’’
Ideally any FPP should have a shelf life of 5 yrs and should
not fall below 90-95% potency under recommended storage.
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Purpose / Importance of Stability Testing
The purpose of stability testing includes
1. Patient Safety. The drug which is being purchased by the patient may be safe
but it’s decomposition product may not be safe or even be toxic.
2. Legal Requirements concerned with the identity, quality, strength and purity
(IQSP) of the drug.
3. to provide evidence on how the quality of a FPP varies with time under the
influence of a variety of environmental conditions such as temperature,
humidity and light.
4. to establish a shelf-life for the FPP.
5. to determine the storage conditions and the in-use stability.
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6. To prevent Economic Loss. If a manufacturer markets an unstable drug
Instability may cause
Undesired change in performance, i.e.
dissolution/bioavailability
Substantial changes in physical appearance of the
dosage form
----Causing product failures
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Specifications of Stability Testing
Should include those attributes that are susceptible to change during
storage and are likely to influence quality, safety and/or efficacy
Should cover as appropriate, the physical, chemical, biological and
microbiological attributes, preservative content and functionality tests
(e.g. for a dose delivery system)
Analytical procedures should be fully validated and stability indicating
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Stability studies at different stages
Stability on pre-formulation batches
Accelerated and long term testing for registration
On-going Stability testing
Follow-up Stabilities
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Accelerated Stability Studies
Stability study is to predict the shelf life of a product by accelerating
the rate of decomposition, preferably by increasing the temperature of
reaction conditions.
With the advancement in branch of kinetics shelf life of dosage form
can be predicted in months based on accelerated stability reports.
It also allows the rapid detection of deterioration of the drug in
different initial formulations of the same product - this is used in
selecting the best formulation from a series of possible choices.
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Arrhenius Equation
It is a well-known fact that raising the temperature increases
the reaction rate.
Quantitatively this relationship between the rate a reaction
proceeds and its temperature is determined by the Arrhenius
Equation.
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Activation Energy
A minimum amount of energy that is required for reaction,
the activation energy, Ea
Just as a ball cannot get over a hill if it does not roll up the hill
with enough energy, a reaction cannot occur unless the
molecules possess sufficient energy to get over the activation
energy barrier.
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Arrhenius Equation………contd
Where,
Ea = activation energy
R = 8.314 [ J · mol -1 · K -1 ]
T = absolute temperature in degrees Kelvin
A = frequency factor
A = p · Z, where Z is the collision rate and p is a steric factor.
Z turns out to be only weakly dependant on temperature.
Thus the frequency factor is a constant, specific for each reaction.
a = number that represents the likelihood that collisions would occur with the
proper orientation for reaction.
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Arrhenius Equation………contd
Taking the natural logarithm of
both sides, the equation
becomes
y = mx + c
When k is determined experimentally at several
temperatures, Ea can be calculated from the slope of a
plot of ln k vs. 1/T 11
ICH Guidelines on Stress Testing
Standard Title and reference
ICH Q1A(R2) Stability Testing of New Drug Substances and
Products (the parent guideline)
ICH Q1B Photostability Testing of New Drug Substances and
Products
ICH Q2A & Validation of Analytical methods
Q2B
ICH Q3A(R) Impurities in New Drug Substances
ICH Q3B(R) Impurities in New Drug Products
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Objectives of Forced Degradation Tests
To identify potential degradants (degradation pathways) of the API and
assess if they can be formed during manufacture or storage of the FPP
(intrinsic stability of the API).
To validate the stability indicating power of the analytical procedures.
To identify stability-affecting factors such as ambient temperature,
humidity and light and to select packing materials, which protect the FPP
against such effects.
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Regulatory or Formal Stability Testing
Minimum time
Storage Relative Testing
period covered by
temperature humidity Frequency
data at submission
(°C) (%) (months)
(months)
Accelerated: 40±2 75±5 6 0, 3, 6
Intermediate: 30±2 65±5 12 0, 6, 12
Long term: 25±2 60±5 12 (6) 0, 3, 6, 9, 12
Stability study should be performed in the claimed 14
commercial packaging (container-closure)
Typical Expected Results
Storage Stress Equivalent Stress Equivalent Stress Equivalent
temperature to 3 year to 2 year to 1 year
(°C)
3–4 2 1
70°C
weeks weeks week
2 1 2
60°C
month month weeks
6 2–4 1
50°C
month months month
1 5–7 2–3
40°C 15
year months months
Significant Changes of FPPs
Some significant changes may occur during accelerated studies. Such as –
1. Any degradation product exceeding its acceptance criterion.
2. Failure to meet the acceptance criteria for appearance, physical attributes,
and functionality test (e.g., color, phase separation, hardness).
3. As appropriate for the dosage form e.g., failure to meet the acceptance
criteria for dissolution for 12 dosage units.
4. A 5% change in assay from its initial value.
Some changes in physical attributes (e.g. softening of suppositories, melting
of creams, partial loss of adhesion for transdermal products) may be expected
under accelerated conditions. 16
Factors affecting Stability
1- Environmental factors
- Temperature - Light
- Oxygen - Moisture
- Carbon dioxide
2- Drugs or excipients in the dosage form
- Particle size of drug
- pH of the vehicle
3- Microbial contamination
4- Trace metal Contamination
5- Leaching from containers
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DRUG STABILITY
There are five types of stability that must be considered
for each drug
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Major 3 Types of stability studies
۞ Physical
۞ Chemical
۞ Microbiological
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Physical stability
Physical stability implies that:
- The formulation is totally unchanged throughout its shelf
life and has not suffered from any changes by way of
appearance, organoleptic properties, hardness, brittleness,
particle size etc.
- It is significant as it affects:
pharmaceutical elegance
drug content uniformity
drug release rate.
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Physical stability............contd.
Likely physical instability
Formulation Effects
problems
1- Loss of flavor Changes in
2- Change in taste
3- Presence of off flavors smell
Oral due to interaction with
plastic bottle or
solutions feel
4- Loss of dye
5- Precipitation or
6- discoloration taste
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Physical stability............contd.
Likely physical instability
Formulation Effects
problems
1. Discoloration due to photo
chemical reaction or oxidation
2. Presence of precipitate due to
interaction with container or Changes in
stopper
Parenteral
3. Presence of “whiskers” appearance
solutions 4. Clouds due to: and
bio-availability
(i) Chemical changes
(ii) The original preparation of a
supersaturated solution
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Physical stability............contd.
Likely physical
Formulation instability Effects
problems
Suspensions 1- settling 1-Loss of drug
content
2- caking uniformity in
different doses
from the bottle
3- crystal growth
2- loss of
elegance.
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Physical stability............contd.
Likely physical instability
Formulation Effects
problems
Emulsions 1- Creaming 1-Loss of drug
content
uniformity in
2- coalescence
different doses
from the bottle
2- loss of
elegance.
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Physical stability............contd.
Coalescence
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Physical stability............contd.
Likely physical
Formulation Effects
instability problems
1. Changes in: 1-Loss of drug
a) Particle size content
b) Consistency uniformity
Semisolids 2- loss of
(Ointments and 2. Caking or elegance
suppositories) coalescence
3-change in drug
3. Bleeding release rate.
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Physical stability............contd.
Likely physical instability
Formulation Effects
problems
Tablets Change in: Changes in
a) Disintegration time
b) Dissolution profile drug release
c) Hardness
d) Appearance (soft and
ugly or become very
hard)
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Physical stability............contd.
Likely physical
Formulation Effects
instability problems
Capsules Change in: Changes in
a) Appearance
b) Dissolution drug release
c) Strength
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Chemical Stability
Chemical stability implies:
The lack/decline of any chemical moiety that is incorporated in
the formulation as the drug, preservatives or any other
excipients.
This decomposition may influence the physical and chemical
stability of the drug.
Chemical stability includes:
Stable against Hydrolysis, Oxidation, Photolysis etc.
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Microbiological Stability
Microbiological stability implies that:
The formulation has not suffered from any microbiological
attack and is meeting the standards with respect to
sterility/lack of contamination.
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Packaging and Stability
The immediate container and closure are particularly
important in affecting product stability.
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Stability of a product is studied in III (3)
Categories
For a drug substance, we need to study 3 categories of
stabilities-
1. Solid state stability of drug only
2. Compatibility studies ( drug+ excipients )
3. Solution phase stability
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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.
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PHOTOLYTIC STABILITY
Many drugs fade or darken on exposure to light and this leads to
an aesthetic problem which can be controlled by using
1 Amber Glass Container
2 Opaque Container
3 Incorporating a Dye
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2. COMPATIBILITY STUDY
3 different techniques are employed in Drug- Excipient Compatibility Screening
1. TLC
2. Differential thermal analysis
3. Diffuse Reflectance Spectroscopy
3. SOLUTION PHASE STUDY
This study assures that the drug substance does not degrade
intolerably when exposed to gastrointestinal fluids.
Stability of dissolved drug in buffers ranging from pH 1-8 is
investigated. 35
