A

Seminar
On
“DRUG STABILITY”

SUBMITTED TO
MUMBAI UNIVERSITY
By
Ms. Swati S. Bharati
(F.Y.M.Pharm)

Under the Guidance of

Dr. BHUSHAN RANE
HOD (Pharmaceutics)

SHRI. D.D. Vispute College of Pharmacy & Research Center

PANVEL
(2016-2017)

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 CONTENTS...
Introduction

Importance And Need Of Stability Testing

Degradation Pathways

Kinetic Stability

Solution Stability

Solid State Stability

pH Stability Profile

Conclusion

Reference
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 INTRODUCTION

STABILITY:
USP defines stability of pharmaceutical product as,
“extent to which a product retains with in specified
limits and throughout its period of storage and use
(i.e. shelf life).

The capacity or the capability of a particular

formulation in a specific container to remain with
in particular chemical , microbiological ,
therapeutically , and toxicological specifications.

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 DRUG STABILITY

Drug stability is defined as the ability of the

pharmaceutical dosage form to maintain the
physical, chemical, therapeutic and microbial
properties during the time of storage and usage by
the patient.

The purpose of stability studies is to provide

evidence on how the quality of the active
substance or pharmaceutical product varies with
time under the influence of a variety of
environmental factor such as temperature,
humidity and light

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 IMPORTANCE

Chemical and physical degradation of drug substances

may change their pharmacological effects, which is then
affecting on their therapeutic and toxicological effect.

Pharmaceuticals products are used therapeutically based

on their efficacy and safety, they should be stable.

Maintenance of quality until the time of usage or until

their expiration date.

The quality should be maintained under the various

conditions that pharmaceuticals encounter, during
production, storage in warehouses, transportation and
storage in hospitals as well as in the home.
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 NEED

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Where stability studies takes place.......
Drug discovery development

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 Types of stability
•

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 TYPES OF STABILITY TESTING
SR. STUDY STORAGE TESTING Minimum
NO CONDITION TIMING Time
. (MONTH) Period
• Stability condition Study Covered By
Data At
Submission
1 LONG TERM 25º C ± 2º C 0, 3, 6, 9, 12, 12 months
(Ambient) 60%RH ± 5% 18, 24, 36, 48,
60.

2 INTERMEDIATE 30º C ± 2º C 0, 3, 6, 9, 12. 6 months

(controlled) 60%RH ± 5%

3 ACCELERATED 40º C ± 2º C 0,1, 2, 3, 6, 9. 6 months

(Short term) 75%RH ± 5%

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 DEGRADATION PATHWAYS
Degradation of active drug leads to lowering of
quantity of the therapeutic agent in the dosage
form

A toxic product formation may takes place due to

decomposition instability of drug product can lead to
a decrease in its BIOAVAILABILITY.

Changes in PHYSICAL APPEARANCE of given

dosage form may takes place.

Degradation may increase or decrease the POTENCY

of drug.

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TYPES OF DEGRADATION PATHWAYS

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 PHYSICAL DEGRADATION
LOSS OF VOLATILE COMPOUNDS

LOSS OF WATER

ABSORPTION OF WATER

CRYSTAL GROWTH

POLYMORPHISMS

COLOUR CHANGES

PHOTOLYSIS

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 LOSS OF VOLATILE COMPOUNDS

Some of volatile components alcohol, ether, Iodine,

volatile oils, Camphor menthol etc escape from the
formulations exposé them degraded.
EXAMPLE:
Some types of tablets (Nitroglycerine tablets)
Aromatic water
PREVENTION:
Such product should be placed in well closed
container.
Temperature should be proper.

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 LOSS OF WATER

Water loss from liquid preparation (o/w emulsion)

leads to changes in stability. It causes crystallization of
drug product .
which may lead to increase in potency , and decrease
in weight.

EXAMPLE :
Water evaporates from na2so4 .BORAX.
Creams: especially oil/water, they become dry by loss
of water.

PREVENTION:
Products should be placed in well-closed container.

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 ABSORPTION OF WATER
Hygroscopic drugs absorb the water from external
atmosphere causing the physical degradation.
Effervescent powders and tablets will deteriorate if
stored in a moist atmosphere.
EXAMPLE:
Powders: Liquification and degradation may occur
as a result of absorption of water
Suppositories which base made from hydrophilic
substances as Glycerin, Gelatin, and polyethylene
glycol. The consistency of these forms becomes
jelly-like appearance.
PREVENTION:
Products should be placed in well-closed container
and in dry place.
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 CRYSTAL GROWTH
Drugs when loose water, become saturated and
crystal growth occurs.
Crystallization is enhanced in porous tablets.In
solutions after super saturation crystal growth
occurs.
EXAMPLE:
Injection of calcium glucconate
In suspensions crystals settle down and caking occurs
and suspension becomes unstable.
Ophthalmic preparations.
PREVENTION:
SOLUTIONS-Stabilizers are added
SUSPENSION-
·Incorporation of surface active agent
·By increasing viscosity of suspending material
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 POLYMORPHISMS

Polymorphs show significant differences in important

physiochemical properties such as solubility, dissolution
rate and melting point. In polymorphic changes crystal
forms are changed. This may cause change in solubility
and possibly crystalline growth in aqueous suspension.
EXAMPLE:
Cortisone acetate suspension.
• PREVENTION:
suspension –suspending agent like methyl cellulose &
ethyl cellulose

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 PHOTOLYSIS
When molecules are exposed to electromagnetic
radiation they absorb light (photons) at characteristic
wavelength which cause increase in energy which can
cause decomposition.

EXAMPLE:
Sodium nitropruside in aqueous solution (which is
administered by IV infusion for management of acute
hypertension).
Iodine
PREVENTION:
Use of amber colored bottles.
Storing the product in dark, packaging in cartons also
act as physical barrier to light.

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 COLOUR CHANGES
Colour changes indicate chemical or photochemical
decomposition of the active ingredients, dyes or other
ingredients. Colour changes are of two types.
1) Loss of colour
2) Development of colour
EXAMPLE:
Phenolphthalein color changes as the PH changes. It is
colorless in acidic solution and pink in basic.
ascorbic acid tablet turn yellowish brown.

• PREVENTION:
• Protect the product from light and air
• Avoid the using reducing substances as additives.

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 CHEMICAL DEGRADATION

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 HYDROLYSIS

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- Involve Acyl – Acid Cleavage.
EXAMPLE :
aspirin ,atropine, physostigmine & procaine..

REACTION:

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• Amide bonds are less susceptible to hydrolysis
than ester bonds.
• The leaving group, an amine, is a poorer leaving
group. It involves cleavage of amide linkage to
give an amine instead of alcohol as in case of
esters.
EXAMPLE:

Chloramphenicol , Barbiturates

REACTION:

RCONHR(amide) + H2O  RCOOH + NH2-R(AMINE)

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• Barbiturates, hydantoins, and imides contain functional
groups related to amides but have a tendency to be
more reactive.
• Barbituric acids such as barbital, phenobarbital and
amobarbital, undergo ring-opening hydrolysis.

REACTION:

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• Benzodiazepines such as diazepam, oxazepam, and
nitrazepam undergo ring opening due to reversible
hydrolysis of the amide and azomethine bonds.
• Benzodiazepinoxazoles(oxazole-condensed
benzodiazepines) such as oxazolam, flutazolam,
haloxazolam, and cloxazolam are undergo ring
opening due to hydrolysis.
REACTION:

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19/11/2016 26
 ISOMERIZATION

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27
 RACEMIZATION

Racemization refers to partial

conversion of one enantiomer
into another. It involves the
optically active form of a drug
into its enantiomorph.

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 EPIMERIZATION

It occurs with the compound

having more than one asymetric
carbon atom in the molecule. At
equilibrium, both epimers are
present, but not in equal
proportion.

EXAMPLE:
Under prolonged storage
solution containing ergometrine
is decomposed by hydrolysis and
isomerized to ergometrinine

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 DECARBOXYLATION

Elimination of CO2 from

compound. Drug substances
having a carboxylic acid group
is sometimes susceptible to
decarboxylation,

EXAMPLE:
4-Aminosalicylic acid
procain

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 ELIMINATION

In elimination, reaction some

groups of the substance is
eliminated.

EXAMPLE:
Trimelamol eliminates its
hydroxymethyl groups and forms
formaldehyde.

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 OXIDATION

Removal of an electropositive atom,

radical or electron, or the addition
of an electronegative atom or
radical. Oxidation is controlled by
environment i.e., light, trace
elements, oxygen and oxidizing
agent.

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 TYPES of OXIDATION

• Oxidation in which the oxygen

presents in the air is involved.
This process proceeds slowly
under the influence of
atmospheric oxygen.

• Oxidation in which removal of

the electron is involved
without presence of O2.

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 PREVENTION

Chelating
agent

Antioxidant
agent

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 MICROBIAL DEGRADATION

Contamination of a product may sometimes

cause a lot of damage and sometimes may not
be anything at all.
-Thus it is dependent on the type of microbe
and its level of toxicity it may produces.
-If parenterals or ophthalmic formulations are
contaminated, it may cause serious harm.

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 Water &
air

Source of
microbial
contamination

Raw Container &

material closure

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 PREVENTION

Suitably designing the containers

Usually using single dose containers

Sticking to proper storage conditions

Adding an antimicrobial substance as

preservative

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 THERAPEUTIC DEGRADATION

Therapeutic effect must be changed due

to hydrolysis, isomerisation or
epimerization .

Example:
Adrenaline

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 Toxicological degradation

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 Kinetic stability

Kinetics deals with the study of the rate at which processes

occur and mechanism of chemical reactions It involves the
study of rate of change and the way in which this rate is
influenced by the concentration of reactants, products, and
other chemical species that may be present, and by factors
such as solvents, pressure, and temperature.
Kinetics applies to:
Stability
Incompatibility
Dissolution
Absorption
Distribution
Drug action at molecular level
Elimination processes

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 Rate & order of reaction

• The speed or velocity of a reaction

with which a reactant or reactants
undergoes a change.
Rate • It is determined by the change in
the concentration of the reactants
or products as a function of time.

• The number of concentrations that

Order of determine rate.
• The way in which the
reaction concentration of the reactant
influences the rate.

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 Types of order of reaction
Zero order of • Rate is constant and is independent
of the concentration of any of the
reaction reactants.

First order of • The reaction rate of change is

reaction proportional to drug concentration.

• Rate depends on the product of two

Second order concentration terms. When you have two
of reaction components reacting with each other or one
component reacting with itself.

• For some reactions, the rate of the reaction

Pseudo order may be independent of the concentration of
of reaction one or more of the reacting species over a
wide range of reactions.
42
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 Overall order of reaction

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 Shelf life

It is defined as the time required for the

concentration of the reactant to reduce to 90% of
its initial concentration .
Represented as t90
the units of time /conc.
t90 = (a-0.9a)/ ko = 0.1 a/ ko
Where,
a = initial concentration.
ko = specific rate constant for zero order
reaction.

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 Shelf life

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 SOLUTION STABILITY

The main purpose of solution stability is identification

of conditions necessary to form a stable solution Study.
Includes – effects of pH, Ionic strength, Co-solvent, light
, temperature and oxygen
Interested experiments at extremes conditions of pH and
temperature (0.01N HCl , water ,0.01N, NaOH all at
90°C).
Aq. Buffers are used to provide wide range with
constant levels of drug, co solvent and ionic strength
Compatible with physiological media

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 SOLID STATE STABILITY

The purpose of solid state stability is

identifications of stable storage conditions for
drug in the solid state and identification of
compatible excipients for a formulations.
Affected by change in purity and crystallinity
Initial bulk lots and newer lots– to be studied
Solid state is slower and difficult to interpret than
solution state
TLC, UV-Vis, fluorescence
Polymorphic changes – DSC, IR or appearance
changes like oxidation – surface discoloration

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 pH STABILITY STUDIES

The pH-stability profile is essential for

understanding how the compound behaves in
different environments and informs formulation
development, process development, drug product
stability and the route of administration of the
molecule.
To develop a pH-stability profile, it is important to
develop stability-indicating assays for the intact
drug at the various pH values to be studied.

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 pH-stability studies

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 CONCLUSION

Pharmaceutical products are assigned a shelf life which

determines the time when a product is considered to be
safe and effective under storage condition.

Stability studies should be based on the basis of

pharmaceutical R&D and regulatory requirements.

Degradation studies reveal the intrinsic chemical

properties of the API while formal stability studies
establish the retest date.

The shelf life is derived from stability studies

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 REFERENCE
http://www.slideshare.net/GajananSanap/stability-studies-58779043on
date15/10/2016

C.V.S Subrahmanyam “Textbook of Physical Pharmaceutics” vallabh

prakashan, second edition, reprint 2007, page no: 13-50, 51-84.

http://www.slideshare.net/bknanjwade/drug-stability-and-stabilization-
techniques. On date 19/10/2016

http://uchpel.vscht.cz/files/uzel/0022888/Chemical%20and%20physical%20deg
radation%202015.pdf. On date 21/10/2016

http://www.slideshare.net/alaaalfayez/stability-tests-for-pharmaceutical-
products on date 19/10/2016

http://cst-kh.edu.ps/staff/mabujamee/wp-content/uploads/2010/10/Unit-4-
Drug-Stability.pdf.

Cartensen J, Marcel Dekker “ Drug Stability Principles and Practises ”Informa

healthcare, third edition,vol 107, 1990, page no:
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