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.
1
 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.
2
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.

3

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

4
 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

5
 Stability studies at different stages
 Stability on pre-formulation batches

 Accelerated and long term testing for registration

 On-going Stability testing

 Follow-up Stabilities

6
 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.
7
 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.

8
 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.

9
 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.
10
 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

12
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.
13
 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
17
 DRUG STABILITY
There are five types of stability that must be considered
for each drug

18
Major 3 Types of stability studies

۞ Physical

۞ Chemical

۞ Microbiological

19
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.

20
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

21
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
22
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.

23
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.

24
Physical stability............contd.

Coalescence

25
 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.
26
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)

27
Physical stability............contd.

Likely physical
Formulation Effects
instability problems

Capsules Change in: Changes in

a) Appearance
b) Dissolution drug release
c) Strength

28
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.

29
 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.

30
Packaging and Stability
The immediate container and closure are particularly
important in affecting product stability.

31
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

32
 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.

33
 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

34
 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