KATHMANDU 

UNIVERSITY
                Dhulikhel,Kavreplanchowk

                                  

        Drug stability and drug degradation

   SUBMITTED BY:-                          SUBMITTED TO:- 
    Puspa Das                                 Shailendra Shakya
    Roll no:-63                          Department of Pharmacy
                                                                                              
                                                         
                    Date of submission:-06/27/2021

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Abstract:-
Drug stability and degradation studies are integral parts of drug development.
Preformulation studies aim to evaluate the intrinsic stability properties of a drug
candidate by deliberate application of stress to cause degradation, and to provide
guidance and suggest remedies for further formulation development. This article
discusses the fundamental concepts of drug chemical stability, common pathways of
drug degradation, physical stability and application of these concepts and techniques
to the assessment of both the chemical and physical stability of pharmaceutical
compounds with its prevention.

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Drug stability and degradation study:-
Drug stability and degradation studies are integral parts of drug development.
Preformulation studies aim to evaluate the intrinsic stability properties of a drug
candidate by deliberate application of stress to cause degradation, and to provide
guidance and suggest remedies for further formulation development.
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:- Stability of pharmaceutical products can be defined as"Extent to which
a product retains within specified limits and throughout its period of storage and
use i.e.shelf life.The capacity or the capability of particular formulation in a
specific container to remain within particular chemical,microbiological
,therapeutically and toxicological specifications.

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.

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 t 90 and the unit is time/conc.
t90=(a-0.9a)=0.1a
ko ko
Where, a = initial concentration of drug product . ko = specific rate constant for
zero order reaction.

Objective of the drug stability:-

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  To gather information during preformulation stage to produce a stable
product.
 To determine the packaging components.
 To provide better storage condition.
 To prevent the drug product from different kind of instability.
 To provide better safety to the patients.
 To determine maximum expiration date/ shelf life.

Factors effecting drug stability: Factors effecting the drug stability are as
under :-

1. Diffusion of drugs and excipients .

2. Molecular binding
3. Additives
4. Particle size (suspension and emulsion)
5. Oxygen
6. Storage closure and containers
7. Light
8. Humidity
9. Moisture
10. Temperature
11.PH

Types of stability:-

1. Physical stability:- The physical stability properties includes appearance,

palatability ,uniformity ,dissolution and suspendability are retained.
2. Chemical stability:- Each active ingredient retains its chemical integrity and
labeled potency within the specified limit.
3. Therapeuratic stability:- Therapeutic activity remains unchanged .
4. Microbiological stability:- Sterility or resistance to microbial growth is
retained according to specified requirement. 
5. Toxicology stability:- No significant increase in toxicity occurs.

TYPES OF DRUG INSTABILITY: Drug instability can be divided into two

major types which is further described in details below:-

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1. Physical degradation
2. Chemical degradation 

1)Physical degradation:-
Physical degradation: “Degradation, which results into the change of physical
nature of the drug.” The types of physical degradation are as below:-
i. Loss of volatile components
ii. Loss of H2O
iii. Absorption of H2O
iv. Crystal growth
v. Polymorphic changes
vi. Color changes

i)Loss of Volatile Components:- Volatile components such as Alcohol ether,

Iodine, volatile oils, Camphor, menthol etc. escape from the formulations.
Examples: a. Aromatic waters
b. Elixirs
c. Spirits
d. Some types of tablets which contain aromatic water (Nitroglycerin
tablets) .

Prevention:-Such product should be placed in well closed container.Temperature

should be proper.

ii) Loss of H2O:- This tendency depends on temperature and humidity of

surrounding environment.
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 type.
c. Creams:- especially oil/water, they become dry by loss of water
d. Pastes
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

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iii)Absorption of H2O: Hygroscopic drugs absorb the water from external
atmosphere causing the physical degradation. Depends on temperature and
humidity of surrounding environment. This phenomena can be seen in the
following pharmaceutical forms:
 Powders: Liquification and degradation may occur as a result of absorption
of water
 Suppositories which base made from hydrophilic substances as Glycerin,
Gelatin, poly ethylene glycol.
 Some deliquescent salts calcium chloride, potassium citrate. The
consistency of these forms becomes jelly-like appearance.
Prevention:-Products should be placed in well closed container and in dry place.

iv)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 glucconate.:In suspensions crystals settle down and
caking occurs and suspension becomes unstable. e.g. Ophthalmic preparations.

Prevention:- Solutions=Stabilizers are added . Suspension=Incorporation of

surface active agent.

V)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.

Prevention:- Suspension=suspending agents like methyl cellulose and ethyl

cellulose. 

2.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.

i)HYDROLYSIS: It is defined as the reaction of a compound with water. 

 Most important in systems containing water such as emulsion , suspension ,

solutions , etc.

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  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:- It 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 esters.

Example of drugs :-Chloramphenicol,barbiturates.

RCONHR(amide)+H2O RCOOH+R-NH2(amine)

Types of Hydrolysis:-It has two types:-

i) 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.
ii) Molecular Hydrolysis: 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:

1) Avoiding contact with moisture at time of manufacture. 

2) Packaging in suitable moisture resistant packs such as strip packs and
storage in controlled humidity and temperature.
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 3) 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.
4) 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 .  
5) 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:-

1) 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
2) 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. 

3)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.

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  By preparing insoluble salt of the drug. E.g. insoluble procaine salt of
benzyl penicillin.
 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.

iii)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.  
 Either the addition of oxygen or removal of hydrogen .
 Occurs when exposed to atmospheric oxygen.
  Oxidation is the loss of electrons while reduction is the gain of electrons.

Types: Oxidation has two types :-

1)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 processes.

2)Photo-oxidation:- 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 acid etc.
Steps Involved in Oxidation Reaction:-

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 i) Initiation : Formation of free radicals is taken place .

R-H  R + [H]

ii) Propogation : here the free radical is regenerated and react with more
oxygen .

R + O2    R-O2

RO2 + RH  ROOH + R

iii) Hydroperoxide Decomposition:-

ROOH  RO + OH

iv)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 ,
etc.

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.

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 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 . Examples:-

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.

e.g. 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
minimized.

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 system.

iv)Photolysis:- 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 :

 Cause decomposition.
 Retained or transferred.
 Be converted to heat .
 Result in light emission at a new wavelength (fluorescence ,
phosphorescence).

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 .

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 Example:- Sodium nitropruside in aqueous solution (which is administered
by IV infusion for 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.

Protection :-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.

v)Decarboxilation:- Elimination of CO2 from a compound.

e.g. · When sol. Of NaHCO3 is autoclaved.
autoclaving the tuberculostatic agent sodium aminosalicylate

vi)Isomerization:- Conversion of an active drug into a less active or inactive

isomer having same structural formula but different stereochemical configuration.
Types: i)Optical isomerization ·
ii)Geometrical isomerization
vii) Polymerization:- Combination of two or more identical molecules to form a
much larger and more complex molecule. e.g. Degradation of antiseptic
formulations and aldehydes is due to polymerization.

viii)Colour change:- Colour change indicate chemical or photochemical

decomposition of active ingredients ,dyes,or other ingredients.Colour changes are
of two types:-

1)Loss of colour

2)Development of colour

Example:-Phenolpthalein colour changes as the PH changes.It is colourless in

acidic solution and pink in basic,ascorbic acid turn yellowish brown.

Prevention:-Protect the product from sunlight and air.Avoid the reducing

substances as additives.

3)Microbial degradation:- Contamination of a product may sometime cause a lot

of damage and sometimes may not be anything at all.Thus it is dependent on the

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type of microbe and its level of toxicity it may produces .If parenterals or
ophthalmic formulations are contaminated,it may cause serious harm.

Source of microbial contamination:-water and air container and closure raw

material.

Prevention:- 1)Suitability designing containers ,

2)Usually using single dose containers,

3)Sticking to proper storage conditions,

4)Adding an antimicrobial substance as preservative.

4)Therapeutic degradation:-Therapeutic effect must be changed due to

hydrolysis,isomerisation or epimerization.Example:-Adrenaline

5)Toxicological degradation:-Some product may be produce toxic during

degradation.Example:-Tetracycline,Chloramphenicol.

Kinetic stability:- Kinetics deals with the study of 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 process

Rate and order of reaction:-

Rate:- The speed or velocity of a reaction with which a reactant or

reactants undergoes a change.It is determined by the change in the concentration
of the reactants or products as a function of time.

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 Order of reaction:- The number of concentration that determine rate.The
way in which the concentration of the reactant influences the rate.

Types of order of reaction:-

1)Zero order of reaction:-Rate is constant and is independent of the concentration

of any of the reactants.

2)First order of reaction:-The reaction rate of change is proportional to drug

concentration.

3)Second orer of reaction:-Rate depends on the product of two concentration

terms.When two components reacting with each other or one component reacting
with itself.

4)Pseudo order of reaction:-For some reactions,the rate of the reaction may be

independent of the concentration of one or more of the reacting species over a wide
range of reactions .

Stability Identifying Assays:-It is a quantitative analytical method which

is based on the characteristic structural ,chemical , biological ,properties of each
active ingredient of drug product and thatcan differentiate between active
pharmaceutical ingredient and its degradationproduct accurately.

Stability Indicating Assay Development:- Developing a stability indicating assay

requires consideration of three aspects ofthe method :-

A. Obtaining a representative SAMPLE.

B. Choosing the separation techniques .

C. Selecting the detectors .

Obtaining A Representative Sample:- Pure drug compound degrades into toxic

compound.

Formulation ----degradation  drug (toxic) + inert (non-toxic).

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Importance of drug stability and degradation :-
 Chemical and physical degradation of drug substance 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 expiration date.
 The quality should be maintained under the various conditions
thatpharmaceuticals encounter,during production,storage in
warehouses,transportation and storage in hospitals as well as in the home.

References:-

1. https://pharmaguidances.com/drug-stability/
2. https://r.search.yahoo.com/_ylt=Awr41D7nSdhgWDwARjZXNyoA;_ylu=Y
29sbwNncTEEcG9zAzEEdnRpZANDMTYxMl8xBHNlYwNzYw--/RV=2/
RE=1624816231/RO=10/RU=https%3a%2f%2fwww.sciencedirect.com
%2fscience%2farticle%2fpii%2fB9780128024478000054%23%3a~%3atext
%3dDrug%2520stability%2520and%2520degradation%2520studies
%2520are%2520integral%2520parts%2cguidance%2520and%2520suggest
%2520remedies%2520for%2520further%2520formulation
%2520development./RK=2/RS=5I1aHcpgwlmxVZkGQkssOLhltus-
3. https://r.search.yahoo.com/_ylt=Awr9NEmOSthg8U0A9pSjzbkF;_ylu=c2Vj
A2ZwLWF0dHJpYgRzbGsDcnVybA--/RV=2/RE=1624816398/RO=11/RU
=https%3a%2f%2fwww.slideshare.net%2fJalalUddin10%2fdrug-stability-
consideration-and-
degradation/RK=2/RS=PMrMfBP_ROwRyRFxWcggAAIBMR8-

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