A Glimpse on Drug Stability
Consideration and Degradation of Drugs
School of Pharmacy
World University of Bangladesh
Drug Stability: The capacity or capability of a particular drug formulation in a
specific container to remain within a particular chemical, microbiological,
therapeutically, physical & toxicological specification in a specified period of
The United States Pharmacopoeia define the drug stability as extent to which a
particular drug product retains intake within a specified limit throughout its
storage and use i.e. shelf life.
Drug Instability: The incapacity or incapability of a particular formulation in a
specific container to remain within a particular chemical, microbiological,
therapeutically, physical & toxicological specification.
Shelf life: Shelf life may be defined as the time required
to degrade a pharmaceutical product to 10% which is
pharmaceutically acceptable. It is indicated as t90 and the
unit is time/conc.
Where, a = initial concentration of drug product .
ko = specific rate constant for zero order reaction.
Factors effecting drug stability:
Factors effecting the drug stability are as under
Storage closure and containers
Particle size (suspension and emulsion)
Diffusion of drugs and excipients .
Objective of the drug stability
To determine maximum expiration date/ shelf life.
To provide better safety to the patients.
To prevent the drug product from different kind of instability.
To provide better storage condition.
To determine the packaging components.
To gather information during preformulation stage to produce a
TYPES OF STABILITY THAT MUST BE
CONSIDERED FOR ANY DRUG
Each active ingredient retains its chemical integrity and labeled potency within the specified
The physical stability properties includes appearance, palatability ,uniformity ,dissolution and
suspendability are retained.
Sterility or resistance to microbial growth is retained according to specified requirement.
Therapeutic activity remains unchanged .
No significant increase in toxicity occurs.
TYPES OF DRUG INSTABILITY:
Drug instability can be divided into two major types-
1. Physical degradation
2. Chemical degradation
“Degradation, which results into the change of physical nature of the
Types: Types of physical degradation are as under
1. Loss of volatile components
2. Loss of H2O
3. Absorption of H2O
4. Crystal growth
5. Polymorphic changes
6. Color changes
1. Loss of Volatile Components: Volatile components such as Alcohol ether,
Iodine, volatile oils, Camphor, menthol etc. escape from the formulations.
a. Aromatic waters
d. Some types of tablets which contain aromatic water (Nitroglycerin tablets)
2. Loss of H2O: This tendency depends on temperature and humidity of surrounding
a. Saturated solution: by loss of water they become supersaturated and precipitate as
crystals is formed
b. Emulsions: Loss of water lead to separation of the two phases and change to other
c. Creams: especially oil/water, they become dry by loss of water
e. Ointments: especially aqueous base ointments
Humectant is added to the previous dosage forms which defined as hydrophilic
substances added to aqueous phase to absorb water from atmosphere and prevent its
loss from the dosage forms. Examples: Glycerin
3. Absorption of H2O: Hygroscopic drugs absorb the water from external atmosphere
causing the physical degradation. Depends on temperature and humidity of surrounding
This phenomena can be seen in the following pharmaceutical forms:
a. Powders: Liquification and degradation may occur as a result of absorption of water
b. Suppositories which base made from hydrophilic substances as Glycerin, Gelatin, poly
c. Some deliquescent salts calcium chloride, potassium citrate.
The consistency of these forms becomes jelly-like appearance
4. Crystal Growth:
In solutions after super saturation crystal growth occurs. Reason may be the fall in
temp and a consequent decrease in solubility of solute. E.g. Injection of calcium
In suspensions crystals settle down and caking occurs and suspension becomes
unstable. e.g. Ophthalmic preparations.
5. Polymorphic Changes: In polymorphic changes crystal forms are changed. A
stable crystal form loosens. This may cause alteration in solubility and possibly crystalline
growth in aqueous suspensions.
CHEMICAL DEGRADATION: Change in the physical nature of the drug is called as chemical
degradation. Chemical degradation of a dosage form occurs through several pathways like –
hydrolysis ,oxidation , decarboxylation , photolysis , racemization .which may lead to lowering of
therapeutic agent in the dosage form ,formation of toxic product , decreased bioavailability etc.
HYDROLYSIS: It is defined as the reaction of a compound with water.
Most important in systems containing water such as emulsion , suspension , solutions , etc.
Also for drugs which are affected by moisture (water vapor) from atmosphere.
It is usually catalyzed by hydrogen ion(acid) or hydroxyl ion(base).
In this active drug is decomposed with solvent.
Usually solvent is water some time reaction may involve pharmaceutical co solvents such as
ethyl alcohol or poly ethylene glycol
Main classes of drugs that undergo hydrolysis are the Esters ,Amide ,Alkali, Acid.
ESTER HYDROLYSIS involve acyl – acid cleavage.
Example of drugs: aspirin ,atropine , physostigmine , procaine.
R-COOR (ester) + H2O R-COOH (acid) + R-OH(alcohol)
AMIDE HYDROLYSIS is more stable than ester , susceptible to
specific and general acid base hydrolysis. It involves cleavage of
amide linkage to give an amine instead of alcohol as in case of
Example of drugs : chloramphenicol , barbiturates .
RCONHR(amide) + H2O RCOOH + R-NH2(AMINE)
Types of Hydrolysis: It has two types
· Ionic hydrolysis
· Molecular hydrolysis
Ionic hydrolysis: Hydrolysis, which occur when the salts of the weak acids &
bases interact with water to give either alkaline or acidic solutions”
e.g. CH3COOK gives alkaline while codeine phosphate gives acidic Sol when
interact with water.
Hydrolysis, which involve the cleavage of drug molecule. It is much slower
and irreversible process. It is catalyzed by hydrogen or hydroxyl ion and
specifically acid or base catalyzed. Rate of decomposition depends on the
pH of the system.
e.g. the local anesthetics, amethocain and benzocaine.
PROTECTION AGAINST HYDROLYSIS:
Avoiding contact with moisture at time of manufacture.
Packaging in suitable moisture resistant packs such as strip packs and storage in
controlled humidity and temperature.
In liquid dosage form since , hydrolysis is acid or base catalyzed , an optimum PH
for max stability should be selected and the formulation should be stabilized at this
PH by inclusion of proper buffering agents.
Hydrolysis of certain drugs such as benzocaine and procaine can be decreased by
the addition of specific complexing agent like caffeine to the drug solutions .
Hydrolysis susceptible drugs such as penicillin and derivatives can be prevented by
formulating them in the dry powder form for reconstitution or dispersible tablets
instead of a liquid dosage form such as solutions or suspensions.
Preventive Measures for Hydrolysis:
Adjustment of pH:
Rate of decomposition is critically dependent upon pH. In the case of acid-base catalyzed
hydrolysis at minimum pH the drug stability is maximum. This can be shown by plotting a
relationship b/w log of the reaction velocity constant for decomposition and pH Maximum
stability for different drugs at dif. pH
Atropine sulphate 3.8, Procaine 3.6, Benzocaine 4.9
Choice of solvent:
More we go away from the water hydrolysis- e.g. Aspirin is unstable in aq. Sol. So it is
formulated in alcohol i.e. propylene glycol.
In some cases non-aq. Solvent increases the instability of product e.g. Cyclamic acid in
aq. sol. Hydrolyze in slow rate while in alcohol high rate.
Addition of surfactants:
Addition of surface-active agents results into significant improvement of drug stability.
This occurs due to the micelles formation. Surface active agents are of two types cationic
and anionic. Anionic micelles are more effective.
Production of insoluble form of drug:
Hydrolysis occur only with that portion of drug which is in aq. Sol.
Hydrolysis can be minimized by
· By making suspensions
· By pH adjustment of the aq. Vehicle.
· By preparing insoluble salt of the drug. E.g. insoluble procaine salt of
· By preparing “transient derivatives” of the drug.
Modification of chemical structure:
Change of chemical structure of a chemical drug may prevent the hydrolysis.
e.g. Alkyl to alkyl chain.
Presence of complexing agent:
By the presence of a compound, which would form water, soluble complex
with drug the rate of decomposition may be decreased. e.g. caffeine
decrease the rate of decomposition of local anesthetics such as benzocaine,
procaine & amethocaine.
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
Occurs when exposed to atmospheric oxygen.
Either the addition of oxygen or removal of hydrogen .
Oxidation is the loss of electrons while reduction is the gain of electrons.
Oxidation has two types
Auto-oxidation: Oxidation in which the oxygen present in the air is involved.
This process proceeds slowly under the influence of atmospheric oxygen e.g. Oil, fats &
unsaturated compound can undergo auto- oxidation.
The reaction between the compounds and molecular oxygen is required for initiating the
chain reaction is called autoxidation .
Free radicals produced during initial reaction are highly reactive and further catalyze the
reaction produced additional free radicals and causing a chain reaction.
Heavy metals such as copper , iron , cobalt , and nickel have been known to catalyze the
oxidative degradation .Heat and light further influence the kinetics of oxidative degradation
Oxidation in which removal of the electron is involved without presence of O2.”
This type is less frequently encountered e.g. It occurs in adrenaline, riboflavin & ascorbic
STEPS INVOLVED OXIDATION REACTION:
INITIATION : Formation of free radicals is taken place .
R--H R. + [H. ]
PROPOGATION : here the free radical is regenerated and react with more oxygen .
R. + O2 R.—O2
R.O2 + RH ROOH + R.
ROOH RO. + OH.
TERMINATION : free radicals react with each other resulting in inactive products.
R.--O2 + X Inactive product
RO2 + RO2 Inactive product
EXAMPLE OF DRUGS DECOMPOSED BY OXIDATION PATHWAYS
Archis oil , clove oil , ethyl oleate ,Heparin , Ascorbic acid , Morphine ,Vitamin A , Vitamin B12 ,
PROTECTION AGAINST OXIDATION
USE OF ANTIOXIDANTS : antioxidants are Mainly of 3 types :
1. The first group probably inhibits the oxidation by reacting with free radicals.
Example – tocopheral , butylated hydroxyl anisole (BHA) , butylated hydroxyl toluene's (BHT).
Concentration 0.001 – 0.1%.
2. The second group comprising the reducing agents , have a lower redox potential than the drug or
other substance that they should protect and are therefore more readily oxidized.
Example –ascorbic acid and iso ascorbic acid , potassium or sodium salts of metabisulfite.
3. The third group, little antioxidant effect themselelf but enhance the action of true antioxidant
Example -- Citric acid , tartaric acid , disodium edetate and lecithin .
USE OF CHELATING AGENT: when heavy metals catalyze oxidation .
Example -- EDTA , citric acid , tartaric acid form complexes.
The presence of reducing agent:
Oxidation of pharmaceutical products can be retarded by the addition of reducing
agents they are equally effective against oxidizing agents and atmospheric oxygen.
· potassium metabisulphites
· sodium metabisulphites
Removal of oxygen:
By limiting the contact of drug with the atmosphere, those oxidative
decompositions dependent upon atmospheric oxygen may be often
The presence of surface active agent:
Oxidizable materials such as oil soluble vitamins essential oils and
unsaturated oils have been formulated as solubilized and emulsified products
Adjustment of pH:
Many of those oxidative decompositions involving a reversible oxidation
reduction process are influenced by the hydrogen ion concentration of the
Exposure to light cause substantial degradation of drug molecule.
• When molecules are exposed to electromagnetic radiation they absorb
light (photons) at characteristic wavelength which cause increase in
energy which can :
Retained or transferred.
Be converted to heat .
Result in light emission at a new wavelength (fluorescence ,
• Natural sun light lies in wavelength range (290– 780nm) of which only
higher energy (UV) range (290 --320) cause photo degradation of drugs.
Example of phototoxic drugs:
Furosemide , acetazolamide , cynocobalamine .
Sodium nitropruside in aqueous solution (which is administered by IV
management of acute hypertension ).
1. If protected from light it is stable to at least 1yr.
2. If exposed to normal room light it has a shelf life of 4 hrs.
1. Use of amber colored bottles .
2. Storing the product in dark , packaging in cartons also act as physical
barrier to light.
3. Coating of tablets with polymer films.
Elimination of CO2 from a compound.
· When sol. Of NaHCO3 is autoclaved.
· autoclaving the tuberculostatic agent sodium aminosalicylate
Conversion of an active drug into a less active or inactive isomer having same structural
formula but different stereochemical configuration.
· Optical isomerization
· Geometrical isomerization
Combination of two or more identical molecules to form a much larger and more
Degradation of antiseptic formulations and aldehydes is due to polymerization.