STABILITY

DEFINITION (USP): Stability is defined as the extent of which a product remains the same properties
& characteristics that it possessed at the time of its manufacture throughout its shelf life (period of storage
& use).

Stability is used to determine:

 Quality of the product

 Shelf life
 Recommended storage conditions

Stability types:

1. Physical stability
2. Chemical stability
3. Microbiological stability

Types of degradation of drug products:

1. Physical degradation
2. Chemical degradation
3. Microbial degradation
4. Photolytic degradation

PHYSICAL DEGRADATION & IT PREVENTIVE MEASURES

Examples of physical degradation in pharmaceutical products are:

a. Evaporation of volatile constituents

b. Loss of water
c. Absorption of water
d. Crystal growth
e. Colour change
f. Polymorphic changes

a. Evaporation of volatile constituents

- Medicinal agents like iodine,camphor, menthol, alcohol, chloroform, anesthetic ether etc. are
volatile in nature and hence gets evaporated from the product during storage.
- Tablet containing nitroglycerine loss potency due to the volatilization of the drug.
- Volatility usually increases with temperature.

Preventive measures: Stirring the product in well closed containers in a cool place.
 b. Loss of water (Degradation)
- Loss of vehicle (water) from the product leads to loss of weight and hence increases in the
concentration of drug which increases the potency.
- Evaporation of water from liquid or semi-liquid preparations (o/w emulsion) cause cracking of
system.
- Loss of water from aq. solutions will give rise to increase in concentration and can lead to crystal
growth.
- Efflorescent substances like borax, caffeine, quinidine sulphate etc. have a natural tendency to
loose water.
- Loss of water depends on temperature and humidity.

Preventive measures: Storing the product in a well closed container in a cool place.

c. Absorption of water
- Absorption of atmospheric moisture causes hydrolysis of drug, increase in weight, and dilution of
dose and hence decreases in potency.
- Deliquescent substances like calcium chloride, potassium carbonate have a natural tendency
absorb water.
- Gelatin capsule absorb moisture and become soft and sticky.
- Glycerin suppository will absorb moisture become opaque.

Preventive measures: Store such product in a well closed container, use of silica gel bags along with
containers or packing materials.

d. Crystal growth
- Fluctuations in the ambient temperature (day and light or seasonal) is responsible for crystal
growth in solutions,, suspensions etc.
- When temperature is lowered, the drug solution becomes supersaturated and leads to precipitation
and crystal growth. Eg; 10% w/v calcium gluconate injections.
- When temperature is lowered I suspensions, the particles slowly become larger in size and finally
forms a solid hard cake. Such injection solution can block the hypodermic needle.
- The metastable crystalline form of a drug slowly converts into more stable crystals with reduced
aq. solubility. This causes precipitation and crystal growth.

Preventive measures:

- Selecting suitable storage conditions to reduce the fluctuations in temperature.

- Increasing viscosity of product
- Addition of surfactant

e. Colour changes
- Colour changes in formulations is a sign of chemical or photochemical decomposition of drug,
dye or any ingredients.
- Tartrazine fades rapidly in the presence of surfactants and light.
 - Indigo carmine fades in the presence of reducing substances like lactose or dextrose.

Preventive measures: It can be prevented by protecting the formulation from air, light, reducing agents
or UV absorbing substances.

f. Polymorphic changes
- Changes between the polymorphic forms can cause changes in solubility and possibly crystal
growth.
- It is essential that the formulated drug should contain a stable crystalline form of drug.

II. CHEMICAL DEGRADATION AND THEIR PREVENTION

The most common causes are :

1. Hydrolysis
2. Oxidation
3. Photochemical decomposition
4. Isomerization

1. HYDROLYSIS
- This problem is most common in system containing water such as emulsion, suspension, solution
etc.
- The main class of drugs that undergo hydrolysis are the esters, amide and the lactams.

a. Ester hydrolysis:
- This reaction involve acyl-oxygen cleavage. The ester hydrolysis whether acid or base catalyzed
can be rep as:

- This equation denotes a second order reaction; it is possible to treat this as pseudo first order
reaction by keeping either the hydrogen of hydroxyl ion concentrations sufficiently high for by
keeping these concentrations constant by the use of buffers.
- Examples of drugs undergo ester hydrolysis are procaine, tetracaine, atropine, physostigmine and
aspirin.

b. Amide hydrolysis
- Amides are relatively more stable than esters and are susceptible to acid-base hydrolysis.
- The reaction involves the cleavage of the amide linkage to give an amine.
 - The reaction can be rep as:

- Examples of drugs are: dibucaine, ergometrine, chloramphenicol and barbiturates.

c. Ring hydrolysis
- Hydrolytic reaction in certain drug proceeds by ring cleavage with subsequent attack by hydrogen
or hydroxyl ion.
- Examples of drugs are: penicillins, cephalosporins, benzodiazepines.

Preventive measures:

1. Hydrolytic reactions in solid drugs products such as tablets, capsules etc. may be prevented by
avoiding the contact with moisture at the time of manufacture, suitable moisture resistant
packaging materials and storage in controlled humidity & temperature conditions.
2. In the case of liquid dosage forms, the rate of hydrolysis can be reduced by maintaining the
optimum pH by using proper buffering agents for maximum stability.
3. Keeping the buffer concentration to minimum required for maintaining the Ph.
4. Hydrolytic reactions can be minimized by altering the dielectric constant of the system by partial
or complete replacement of water with non-aqueous solvent such as alcohol, glycerine and
propylene glycol.
5. Hydrolysis of certain drugs such as benzocaine or procaine can be decreased by addition of
specific complexing agents like caffeine to the drug solutions.
6. Molecular solubilization of certain drugs such as benzocaine by the use of surfactants protects
them from hydrolysis.
7. Hydrolysis of susceptible drugs such as penicillins and its derivatives can be prevented by
formulating them in the form of dry powder for reconstitution or dispersible tablets instead of a
liquid dosage form such as solution or suspension.
8. Refrigeration of drugs and drug solutions also retard hydrolysis.

2. OXIDATION
- Instabilities of a number of pharmaceutical preparations are due to oxidative degradation of the
active ingredients of these preparations when exposed to atmospheric oxygen.
- Autoxidation is the common form of oxidative degradation that occurs in many of the
pharmaceutical preparations and involves a free radical chain process. In autoxidative
degradation, only a small amount of oxygen is required for initializing the reaction and therefore
oxygen concentration is relatively unimportant. The free radicals produced during the initial
reactions are highly reactive and further catalyze the reaction to produce additional free radicals
and causing a chain reaction.
- Factors catalyze the oxidative degradation: heavy metals like copper, iron, cobalt and nickel;
some solvents other than water, heat and light.
- Examples of drugs: morphine, ascorbic acid, epinephrine, vitamin A, D and K.

Preventive measures:

1. Addition of suitable antioxidants prevents oxidation in pharmaceutical preparations.

2. Most oxidative degradation in pharmaceutical preparations compounds are autoxidative, it is
necessary to include antioxidants which will not only react with the free radicals but also
terminate the chain propagation reaction by forming relatively stable free radicals. Water soluble
antioxidants acts by getting oxidized preferentially while oil soluble antioxidants preventing the
chain propagation reaction.
Examples of antioxidants:
- Aq. system: sodium sulphite, sodium metabisulphite, ascorbic acid etc.
- Oily system: tocopherol, propyl gallate, butylated hydroxyl toluene (BHT), butylated
hydroxyl anisole etc.
3. The effectiveness of antioxidants can b increased by the use of synergists such as chelating agents
which react with impurities like heavy metals which may catalyze the oxidation.
4. When oxidation is catalyzed by hydrogen or hydroxyl ions, the pH of optimum stability must be
ensured.
5. Replacement of air from the container of the preparation b inert gas.
6. Protection from light and storage at low temperature.

3. PHOTOLYSIS
- Many pharmaceutical compounds undergo degradation when exposed to light. Exposure
to light produces oxidation-reduction, ring rearrangement and polymerization.
- Photochemical reaction may be accompanied by thermal reaction. The thermal reaction
once induced by light may continue after the light source has been withdrawn.
- The possible orders of photochemical reactions are second, first and zero order.
- Examples of drugs: ascorbic acid, cyanocobalamine, riboflavin, folic acid, nifedipine etc.
 Preventive measures:

- Use of amber colored containers or stored the product in dark.

- Packaging in cartons act as a physical barrier to light.
- Coating of tablets with polymer films contains UV absorbers.

4. ISOMERIZATION
- Isomerization is the process of conversion of a drug into its optical or geometric isomers.
Such a conversion from one form to another may result in serious loss of therapeutic
activity.
- Examples:
o The loss of activity of adrenaline solution at low pH due to the conversion of its
therapeutically active levorotatory form to the less active dextrorotatory from.
o Epinephrine shows acid-catalyzed racemisation with loss of therapeutic activity.
o Epimerization of tetracycline in acidic conditions to form less active epi-
tetracycline.
o Base catalyzed epimerization of pilocarpine.
o Cis-trans isomerisation of Vitamin A from its therapeutically active cis-isomer to
less active trans isomer.

III. MICROBIAL DEGRADATION AND THEIR PREVENTION

It is defined as the deterioration of pharmaceutical products by contaminant microbe. Contamination from

microorganism is a big problem for all the formulations containing moisture, but it can also be a problem
for solid dosage forms also. If some natural polymers are used since natural polymers are fertile sources
of microorganisms.

Sources of microbial contamination

a. Water (eg; pseudomonas)

b. Air (eg; mould spores, bacterial spores, yeast)
c. Earths (eg; anaerobic spore formers)
d. Raw materials (eg; micrococci)
e. Pigments (eg; salmonella)
f. Gums (eg; actinomyces)
g. Animal products (eg; salmonella)
h. Personnel (eg; streptococci)
Stages of contamination:

Microbial contamination occurs either during the time of

a. Manufacture of formulation
b. Usage of formulation

During manufacture

The following factors can cause the microbial contamination during the time of manufacture.

- Raw materials (water and minerals of natural origin)

- Environment of pharmaceutical industry (wet sites, cleaning equipment)
- Packaging (cardboard, corks, papers etc)
- Container that are frequently reused
- Repacking of products purchased in bulk into smaller containers
- Processing
- Storage
- Temperature

Microbial contamination during the usage of formulation

a. Human sources
o Induces patient contamination
o Use of disposable applicators and spoons for topical and oral products
o Improper handling
o Hand washing and creams used by hand
b. Environmental source
o Air born contamination
o Water borne contamination
c. Equipment source
o Equipments for drug administration
o Hospital equipments

Pharmaceutical ingredients those are susceptible to microbial degradation

1. Therapeutic drugs
2. Sweetening, flavoring and coloring agents
3. Humectants
4. Organic polymers
5. Preservatives and disinfectants
6. Surface active agents

Therapeutic drugs
 - Alkaloids : Morphine, atropine
- Pain killers : Aspirin, paracetamol

Sweetening, flavoring and coloring agents

- Sugar
- Coloring agents : Amaranth, tartrazine
- Flavors: Peppermint water

Humectants

- Humectants are ingredients used to maintain the wettability of formulations or to prevent dry off.
Eg; Glycerine, sorbitol.

Organic polymers

- Ager, pectin, cellulose, PEG.

Preservatives and disinfectants

- Many preservatives and disinfectants can be metabolized by a wide variety of gram –ve bacteria
but at concentration below their effective use levels.

Visible signs of microbial degradation

- Loss of viscosity and sedimentation due to then polymerization of suspending agents

- pH change
- Gas production
- Unpleasant odour and taste
- Discoloration of product by microbial growth of various shades.
- Microbial induced polymerization of sugars and surfactant molecules can produce shiny, viscous
masses in syrups, shampoos and creams.
- Metabolism of surfactants by microbes in o/w emulsions reduce stability and accelerate creaming
of oil globules.

Factors that affect the growth of microorganisms in a formulation

- Type and size of microorganisms (inoculums)

- Nutritional factors
- Moisture content (water activity)
- Redox potential
- Storage temperature
- pH
- packaging design

Preventive measures for microbial growth

 1. preservatives (Antimicrobials)
o use of preservatives will inhibit the growth of microorganism in the formulation during
storage or during multidrug application.
o The inclusion of preservatives may be unnecessary in case of tablets, capsules and
powders.
Qualities and features of an ideal preservative
- It should be physically, chemically and therapeutically compatible with other ingredients of the
formulation.
- It should not produce irritation or toxicity at the concentrations used.
- It should be very effective in preventing the growth of microorganisms most likely contaminate
the preparation.
- It should have good aqueous solubility (i.e; water solubility) since water is the media for
microbial growth.
- It should have adequate stability in heat and prolonged storage, with no chemical decomposition
or volatilization during the desired shelf life.
- It should remain undissociated at the pH of the formulation.
- It must be economical (cheap).
- It must have an acceptable odor and color.
- It should not be affected by the product container and closure.

Types of preservatives used in pharmaceutical preparations

Preparations Preservatives used Concentration (% w/v)

Injections Phenol 0.5
Cresol 0.3
Chlorocresol 0.1
Tablets Methyl paraben 0.1
Creams Parabens 0.1-0.2
Chlorocresol 0.1
Dichloro benzyl alcohol 0.05-0.2
Phenyl mercuric nitrate 0.001
Mixtures Chloroform 0.25
Benzoic acid 0.1
Methyl paraben 0.1
Alcohol 12-20
Eye drops Chlorhexidine acetate 0.01
Benzalkonium chloride 0.01
NB: Parenteral and ophthalmic preparations have to be totally free from microorganism, i.e they must be
sterile.

2. Proper storage of formulations: The product must be stored in a tight container protected from light
and moisture. They should be stored in cool, dry place.
3. Hygienic condition should be maintained during the disposal of drug from container. If it is a
multi-dose formulations (eg; in wide mouth containers) can get easily contaminated.
4. High temperature storage conditions should be prevented since certain rise in temperature can
catalyze microbial metabolic reactions.