By
Dr. Nehal Aly Afifi
Professor of Pharmacology
Faculty of Vet. Med.
Cairo university
Drug Stability
Drug Stability
Definition:
Drug stability means the ability of pharmaceutical
dosage form (PDF) to maintain the physical, chemical,
therapeutic & microbial properties during the time of
storage & usage by patients.
Stability measured by the rate of changes that occur in
PDF.
Expiry date: means that drug can not be used after this
date because the conc. of drug decreased & become
lower than the therapeutic conc.
Shelf life of 2-3 years is generally desired.
Q10 Method of Shelf Life Estimation.
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Expiry date
After opening of the drug container,
the expiry date will be shorter . E.g.:
1.Eye drops: can be used for one month after opening dropper.
2. Syrups & suspension of antibiotics : can used for one week
by storage in room temp.and for 2weeks by storage in 4◦C.
3. Ampoules must be used immediately but the multidose vials
are stable for 24 hrs. for the presence of preservatives.
4. Tablets and capsules remain stable in the package, but after
removal the expiry date will change.
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Factors affecting Drug Stability
1-Temperature:
High temp. accelerate oxidation,
reduction & hydrolysis reactions
which lead to drug degradation.
- 2. pH:
Acidic & alkaline pH influence the
rate of decomposition of most drugs.
Many drugs stable between pH 4 & 8.
Weekly acidic & basic drugs show
good solubility when are ionized and
also decompose faster.
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Factors affecting Drug Stability(Cont.)
3. Moisture:
Water catalyze chemical reactions as oxidation, hydrolysis
and reduction reaction.
Water promotes microbial growth
4. Light: affect stability through its energy or thermal effect.
5. Pharmaceutical dosage forms:
Solid dosage forms more stable than liquid dosage forms
6. Concentration: rate of drug degradation is constant for
solutions of the same drug with different conc.
So ratio of degraded part in diluted sol. Is bigger than in of
concentrated Sol.
Stock Sol. At high concentration →The stability is high. 11/7/2016 Prof. Nehal Afifii
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Factors affecting Drug Stability (Cont.)
7. Drug incompatibility:
Reactions between components of PDF itself or
between components and cover of container.
8. Oxygen: Exposure of drug formulations to oxygen
affect their stability .
Enhancing Stability of Drug Products:
Excipients are added to protect the drug such as:
Antioxidants
Preservatives
Chelating agents
Buffering agents
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Types of stability studies
Physical stability
Chemical stability
Microbiological
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1. Physical stability
Physical stability implies that:
The formulation is totally unchanged throughout its shelf life
and has not suffered any changes by way of appearance,
organoleptic properties, hardness, brittleness, particle size .
It is significant as it affects:
pharmaceutical elegance
drug content uniformity
drug release rate.
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Physical instabilities possibilities 1. Crystal formation in PDF:. cause
a. Polymorphism phenomena i.e. Chloramphenicol
(change of amorphous to crystalline form).
2. Loss of volatile subs. from PDF (e.g. Aromatic waters,
Elixirs , Spirits, and Nitroglycerin tablet ).
3. Loss of water in the following PDF
a. Saturated sol.→ supersaturated & ppt as crystals,
b. Emulsions → separation of the two phases
c. Creams(oil/ water), Pastes. Ointment
Humectants (e.g; Glycerin added as hydrophilic subs)
4. Absorption of water: in the following PDF
a. Powders →Liquefaction, b.Suppositories →jelly-like
appearance in consistency.
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The Instability problems
in different formulations
Formulation Instability problems Effects
Oral
solutions
1- Loss of flavour
2- Change in taste
3- Presence of off flavors
due to interaction with
plastic bottle
4- Loss of dye
5- Precipitation
6- Discoloration
Change
in smell
or feel or
taste
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Physical stability (Cont.)
Formulation Likely physical
instability problems
Effects
Emulsions 1- Creaming
2- coalescence 1- Loss of drug
content uniformity
in different doses
from the bottle .
2- loss of
elegance.
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Physical stability (Cont.)
Formulation Likely physical
instability problems
Effects
Suspensions 1- settling
2- caking
3- crystal growth
1-Loss of drug
content uniformity
in different doses
from the bottle
2- loss of elegance.
Physical stability (Cont.)
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Coalescence
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Formulation Instability Problems Effects
Parenteral
solutions
1. Discoloration ( due to
photo chemical
reaction or oxidation)
2. Presence of precipitate
(due to interaction
with container or
stopper)
3. Clouds: will appear in
DF due to :
a. Chemical changes.
b. The product Solubility
is exceed.
Change in
appearance &
in
bioavailability
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Physical stability (Cont.)
Formulation Likely physical
instability problems
Effects
Semisolids :
(Ointments &
suppositories)
1. Changes in:
a) Particle size.
b) Consistency.
2. Caking or
coalescence.
3. Bleeding.
1-Loss of drug
content uniformity.
2- loss of elegance.
3-change in drug
release rate.
Physical stability (Cont.)
Formulation Likely physical instability
problems
Effects
Tablets Change in:
a) Disintegration time.
b) Dissolution profile.
c) Hardness.
d) Appearance (soft and ugly
or become very hard)
Changes
in drug
release
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Physical stability (Cont.)
Formulation Likely physical
instability problems
Effects
Capsules Change in:
a) Appearance
b) Dissolution
c) Strength
Change in drug
release
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2. Chemical stability
Chemical stability implies:
The lack of any decomposition in the 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.
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Hydrolysis means “splitting by water’’
Some Functional Groups Subject to Hydrolysis
Mechanisms Of Degradation
1- Hydrolysis:
Drug type
Examples
Esters
Aspirin, alkaloids – Nitroglycerin-
Lactones
Pilocarpine - Spironolactone
Amides
Chloramphenicol
Lactams
Penicillins - Cephalosporin's
Imides
Glutethimide
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Oxidation of inorganic & organic compounds explained by a
loss of electrons & the loss of a molecule of hydrogen
Some Functional Groups Subject to Autoxidation
Mechanisms Of Degradation
2- Oxidation
Functional group
Examples
Catechols
Catecholamines (dopamine)
Ethers
Diethylether
Thiols
Dimercaprol (BAL)
Thioethers
Chlorpromazine
Carboxylic acids
Fatty acids
Mechanisms Of Degradation
3- Photolysis
Photolysis means: decomposition by light
E.g. Sodium nitroprusside is administered by IV
infusion for management of acute hypertension.
If the solution is protected from light, it is stable for at
least 1 year;
if exposed to normal room light, it has a shelf life of
only 4 hours.
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Mechanisms Of Degradation
Relationship between wavelength and associated
energy of various forms of light.
Type of radiation Wavelength Energy
U.V.
Visible
I.r.
50 – 400
400 – 750
750 – 10,000
Kcal mol-1
287 – 72
36 - 1
Conventional tungsten filament light bulbs are safe & do not
contribute to photolysis.
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Mechanisms Of Degradation
Photolysis is prevented by:
1- suitable packing in amber coloured bottles
2- cardboard outers
3- aluminium foil over wraps
Factors Affecting Rates Of Degradation:
1- PH
The acidity or alkalinity of a sol. has a profound influence on the
decomposition of drug compound.
Aspirin buffered sol. maximum stable at a pH of 2.4,. above a pH of
10 the decomposition rate rapidly increases.
PH also influence rate of oxidation. system is less readily oxidized
when the pH is low
Factors Affecting Rates Of Degradation
2- Complexation:
Complex formation reduce rate of hydrolysis & oxidation.
E.g. caffeine complexes with local anesthetics, as benzocaine, &
procaine to cause a reduction in their rate of hydrolytic degradation
3- Surfactants:
Nonionic, cationic and anionic surfactants when added to sol.
containing drugs form micelle & drug particles become trapped in
the micelle.
The hydrolytic group as OH cannot penetrate this micelle cover &
reach drug particles, so hydrolysis rate decrease.
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Factors Affecting Rates Of Degradation
4- Presence of heavy metals:
Heavy metals, such as copper, iron, cobalt and nickel
increase the rate of formation of free radicals and enhance
oxidative decomposition.
5- Light and humidity:
Light, especially ultraviolet light enhances photolysis and
humidity enhances hydrolytic decomposition.
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Stabilization of drugs against
hydrolysis, oxidation and photolysis
1- Temperature:
All the drug products are stored at suitable temperatures to
avoid thermal acceleration of decomposition.
3 varieties of temp. suggested for storage of drug products.
Room temp, cool storage & cold storage.
2- Light:
Light sensitive materials are stored in ambered colour bottles
3- Humidity:
Packing materials are chosen (usually glass & plastic) to
prevent exposure of drug products to high humid condition.
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Stabilization of drugs against hydrolysis,
oxidation and photolysis
Antioxidants commonly used for
Aqueous systems Oil systems
Sodium Metabisulfite
Sodium Thiosulfate
Ascorbic acid
Ascorbyl palmitate
Butylaled hydroxy toluene
Butylated hydroxy anisole
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Stabilization of drugs against hydrolysis,
oxidation and photolysis
4- Oxygen:
Proper packing keeping the oxygen content of sol. less &
leaving very little head space in the bottle above the drug
products are methods to fight against oxidation.
5- Chelating Agents:
Chelating agents form complexes with heavy metal ions &
prevent them from catalyzing oxidative decomposition
E.g. ethylenediamine tetracetic acid (EDTA) derivatives &
salts, citric acid and tartaric acid.
6- Solvents:
By addition of a suitable solvent hydrolysis rate decreased.
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3. Microbiological stability
Microbiological stability implies that:
The formulation has not suffered from any
microbiological attack and is meeting the standards with
respect to lack of contamination/sterility.
Sources of Microbial Contamination:
1. Water. 2. Air
3. Raw materials, containers and closures.
4. Personnel. 5. Instruments and apparatus.
2 strategies followed in manufacture of Microbiological
stabile, acceptable preparations:
1- prevent contamination of the product.
2- The addition of Preservatives.
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To prevent contamination to formulations
Parenterals considered as one class in
microbiological stability & the rest of DF as one class.
Parenterals either terminally sterilized or
manufactured by aseptic procedure.
To prevent contamination to formulations during
storage:
(1) Suitably designing the containers.
(2) Usually using single dose containers.
(3) Sticking to proper storage conditions.
(4) Adding antimicrobial substance as preservative.
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Preservatives used in Pharmaceutical Preparations
Preparation Preservative Conc. (% w.v)
Injections Phenol
Cresol
Chlorocresol
0.5
0.3
0.1
Eye drops Chlorhexidine acetate
Benzalkonium chloride
0.01
0.01
Mixtures Benzoic acid
Methyl paraben
Alcohol
0.1
0.1
12-20
Creams
Parabens
Chlorocresol
0.1-0.2
0.10
Tablets
Methylparaben 0.1
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Parenterals & ophthalmic preparations have to
be totally free from microorganisms (Sterile)
1. Placing a suitable preservative or combination of
preservatives in the products.
2. Storing the products properly.
3. Stoppering them properly by aseptic procedures.
If any microbial growth takes place & is observed, the
product condemned and its entire batch is recalled.
The storage of Parenterals & ophthalmic preparations
are done under conditions recommended by WHO;
which prescribe temp. humidity, cleanliness as well as
color of the walls of the room.
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Packaging And Stability
The immediate container & closure are particularly
important in affecting product stability.
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Packaging and Stability
Packing of the drug product is very important when its
stability is being considered.
The immediate container and closure are particularly
important in affecting product stability.
Four types of containers commonly utilized for packing
drug products:
Glass, Plastic, rubber(natural and synthetic) and metal.
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1. Glass
Glass is resistant to chemical and physical changes
Glass is the most commonly used material.
Glass has the Limitations of:
1. Its alkaline surface raise pH of the product.
2. Ionic radicals present in the drug precipitate
insoluble crystals from the glass.
3- The clarity of glass Permits the transmission of light
(high energy wave length) w. Accelerate decomposition.
Overcome:1. By the use of Borosilicate glass (contain
fewer reactive alkaline ions).
2. By the use of buffers.
3. . By the use of Amber coloured glass
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2. Plastics
Plastics include a wide range of polymers
of varying density & moleculer weight,
each possing different Physicochemical
characteristics.
The problems with plastic are:
1. Migration of drug through plastic
into the environment.
2. Transfer of environmental moisture, oxygen, and other
elements into the pharmaceutical product.
3. Leaching of container ingredients into drug.
4. Adsorption or absorption of active drug or excipients
by the plastic.
Packaging And Stability
3. Metals
Various alloys & aluminium tubes may be utilized as
containers for emulsions, ointments, creams & pastes.
Limitation:
They may cause corrosion & precipitation in drug product.
Overcome: Coating the tubes with polymers may reduce
these tendencies.
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Packaging And Stability
4. Rubber
Rubber also has problems of extraction of drug ingredients
and leaching of container ingredients described by plastic.
The use of neoprene, butyl or natural rubber , in
combination with certain epoxy, Teflon or vanish coatings
reduce → drug-container interactions.
The pretreatment of rubber vial stoppers and closures with
water and steam reduces potential leaching.
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