Drug Stability: Dr. Nehal Aly Afifi

Drug Stability
By
Dr. Nehal Aly Afifi
Professor of Pharmacology
Faculty of Vet. Med.
Cairo university
drnehal_afifi@cu.edu.eg
Drug Stability
2
 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.
Prof. Nehal Afifii 11/7/2016
Expiry date
3
 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.
Factors affecting Drug Stability
4
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.
Factors affecting Drug Stability(Cont.)
5
 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.
Factors affecting Drug Stability (Cont.)
6
 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

Types of stability studies
7
Physical stability
Chemical stability
Microbiological

1. Physical stability
8
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.

Physical instabilities possibilities
9
 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.
The Instability problems
in different formulations
10
Formulation Instability problems Effects
Oral 1- Loss of flavour Change

2- Change in taste
solutions in smell
3- Presence of off flavors
due to interaction with or feel or
plastic bottle taste
4- Loss of dye
5- Precipitation
6- Discoloration
Physical stability (Cont.)
11
Likely physical Effects
Formulation
instability problems
Emulsions 1- Creaming 1- Loss of drug
2- coalescence
content uniformity
in different doses
from the bottle .
2- loss of
elegance.

Formulation Likely physical Effects
Suspensions 1- settling 1-Loss of drug
2- caking content uniformity
3- crystal growth in different doses

from the bottle
2- loss of elegance.
Prof. Nehal Afifii 12 11/7/2016

13
Coalescence

Formulation Instability Problems Effects
Parenteral 1. Discoloration ( due to Change in

photo chemical
solutions reaction or oxidation) appearance &
2. Presence of precipitate
in
(due to interaction
with container or bioavailability
stopper)
3. Clouds: will appear in
DF due to :
a. Chemical changes.
b. The product Solubility
is exceed.

Semisolids : 1. Changes in: 1-Loss of drug
(Ointments & a) Particle size. content uniformity.
suppositories) b) Consistency.
2- loss of elegance.
2. Caking or
coalescence. 3-change in drug
3. Bleeding. release rate.

16
Likely physical instability Effects
Formulation
problems
Tablets Change in: Changes
a) Disintegration time. in drug
b) Dissolution profile. release
c) Hardness.
d) Appearance (soft and ugly
or become very hard)

17

Capsules Change in: Change in drug
a) Appearance release
b) Dissolution
c) Strength

2. Chemical stability
18
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.

Mechanisms Of Degradation
1- Hydrolysis:
Hydrolysis means “splitting by water’’
Some Functional Groups Subject to Hydrolysis
Drug type Examples
Esters Aspirin, alkaloids – Nitroglycerin-
Lactones Pilocarpine - Spironolactone
Amides Chloramphenicol
Lactams Penicillins - Cephalosporin's
Imides Glutethimide
2- Oxidation
Oxidation of inorganic & organic compounds explained by a
loss of electrons & the loss of a molecule of hydrogen
Some Functional Groups Subject to Autoxidation
Functional group Examples
Catechols Catecholamines (dopamine)
Ethers Diethylether
Thiols Dimercaprol (BAL)
Thioethers Chlorpromazine

Carboxylic acids Fatty acids
21
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.

Relationship between wavelength and associated
energy of various forms of light.
Type of radiation Wavelength Energy
U.V. 50 – 400 Kcal mol-1
Visible 400 – 750 287 – 72
I.r. 750 – 10,000 36 - 1
Conventional tungsten filament light bulbs are safe & do not

contribute to photolysis.
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
24
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.
Factors Affecting Rates Of Degradation
25
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.

Stabilization of drugs against
hydrolysis, oxidation and photolysis
26
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.
Stabilization of drugs against hydrolysis,
oxidation and photolysis
27
Antioxidants commonly used for
Aqueous systems Oil systems
Sodium Metabisulfite Ascorbyl palmitate
Sodium Thiosulfate Butylaled hydroxy toluene
Ascorbic acid Butylated hydroxy anisole

Stabilization of drugs against hydrolysis,
oxidation and photolysis
28
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.
3. Microbiological stability
29
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.
To prevent contamination to formulations
30
 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.
Preservatives used in Pharmaceutical Preparations
Preparation Preservative Conc. (% w.v)

Injections Phenol 0.5
Cresol 0.3
Chlorocresol 0.1
Eye drops Chlorhexidine acetate 0.01
Benzalkonium chloride 0.01
Mixtures Benzoic acid 0.1
Methyl paraben 0.1
Alcohol 12-20
Creams Parabens 0.1-0.2
Chlorocresol 0.10
Tablets Methylparaben 0.1
Prof. Nehal Afifii 31
11/7/2016
Parenterals & ophthalmic preparations have to
be totally free from microorganisms (Sterile)
32
 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.
Packaging And Stability
33
 The immediate container & closure are particularly
important in affecting product stability.

Packaging and Stability
34
 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.

1. Glass 35
 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
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.

37
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.

38
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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Drug Stability

 After opening of the drug container,

the expiry date will be shorter . E.g.:

2. Syrups & suspension of antibiotics : can used for one week

3. Ampoules must be used immediately but the multidose vials

4. Tablets and capsules remain stable in the package, but after

Prof. Nehal Afifii 11/7/2016

Physical stability implies that:

drug content uniformity

drug release rate.

Prof. Nehal Afifii 11/7/2016

Formulation Instability problems Effects

Oral 1- Loss of flavour Change

Prof. Nehal Afifii 11/7/2016

2- caking content uniformity

3- crystal growth in different doses

Prof. Nehal Afifii 12 11/7/2016

Prof. Nehal Afifii 11/7/2016

Parenteral 1. Discoloration ( due to Change in

Prof. Nehal Afifii 14 11/7/2016

Semisolids : 1. Changes in: 1-Loss of drug

(Ointments & a) Particle size. content uniformity.

Prof. Nehal Afifii 15 11/7/2016

Tablets Change in: Changes

a) Disintegration time. in drug

b) Dissolution profile. release

d) Appearance (soft and ugly

or become very hard)

Formulation Likely physical Effects

Capsules Change in: Change in drug

Prof. Nehal Afifii 11/7/2016

Chemical stability implies:

The lack of any decomposition in the chemical moiety

This decomposition may

influence the physical and

Chemical stability of the drug.

Prof. Nehal Afifii 11/7/2016

Drug type Examples

Esters Aspirin, alkaloids – Nitroglycerin-

Lactones Pilocarpine - Spironolactone

Lactams Penicillins - Cephalosporin's

Functional group Examples

Catechols Catecholamines (dopamine)

Thiols Dimercaprol (BAL)

Prof. Nehal Afifii 20 11/7/2016

Photolysis means: decomposition by light

E.g. Sodium nitroprusside is administered by IV

If the solution is protected from light, it is stable for at

if exposed to normal room light, it has a shelf life of

Prof. Nehal Afifii 11/7/2016

Visible 400 – 750 287 – 72

I.r. 750 – 10,000 36 - 1

Conventional tungsten filament light bulbs are safe & do not

Nonionic, cationic and anionic surfactants when added to sol.

The hydrolytic group as OH cannot penetrate this micelle cover &

4- Presence of heavy metals:

Heavy metals, such as copper, iron, cobalt and nickel

5- Light and humidity:

Light, especially ultraviolet light enhances photolysis and

Prof. Nehal Afifii 11/7/2016

Light sensitive materials are stored in ambered colour bottles

Antioxidants commonly used for

Aqueous systems Oil systems