Drug Stability 1

Drug Stability: Stability of a Pharmaceutical Product may be defined as the capability of

a particular formulation, in a specific container system to remain within its physical,
chemical, microbiological, therapeutic, and toxicological specifications.
Importance of the study of Stability: Pharmaceutical products and preparations often
exhibit chemical or physical instabilities. The determination that results from such
instabilities may lead to
a. A reduced activity of the preparation
b. The formation of toxic reaction products
c. The formation of inelegant or unstable product, e.g., a broken emulsion.
d. Stability is an important parameter from the viewpoint of the patient,
pharmacist or physicians.
So, a study of the stability of the pharmaceutical products and stability testing techniques
is essential for the following three major reasons: (i) Ensure the safety of the patient
(ii) To maintain the activity of the product
(iii) To maintain sales
(i) Ensure the safety of the patient: It is important because the patient receives a uniform
dose of drug throughout the whole of the shelf life of the product. This is of particular
importance when preparing parental solutions. Since injection frequently involves a
greater risk than other forms of drug administration.
(ii) To maintain the activity of the product: To maintain the activity of the product,
consideration must be given to relevant legal requirements concerned with the identity,
strength, purity and quality of the drug.
(iii) To maintain sales: Such a study is important to prevent the economic repercussions
or driving back of marketing an unstable product. The sale of such product is hardly the
best advertisement for a manufacture and subsequent withdrawal and reformulation the
drug may lead to considerable finance loss.
Shelf life: Manufacturing Date to Expired Date is referred as shelf life

ASIF HASAN NILOY

GB Pharm24 (3rd Semester)

Drug Stability 2
Degradation: The word degradation means Reduce from higher to lower rank.
Routes of Degradation: A drug or pharmaceutical product can be decomposed by
following three ways: 1) Physical Degradation
2) Chemical Degradation
3) Others (Photochemical, Therapeutic degradation etc.)
1) Physical Degradation: Physical degradation is the visible, recognizable change in one or
more ingredients. Such in color or forms etc. physical degradation occurs in the following
ways: a) Loss of volatile constituents
b) Loss of water
c) Absorption of water
d) Crystal growth
e) Polymorphic changes
f) Color changes
g) Pressure
h) Contact
a) Loss of volatile constituents: A wide range of materials e.g. iodine, Camphor, menthol,
alcohol, and anesthetic ether are volatile at room temperature and may lost from
pharmaceutical preparations. It causes the decrease potency of the preparations.
Ex Tablets containing nitroglycerin may lose potency because of volatilization of the
drug.
Protection: i) Placing the products in well-closed container.
ii) Storage the drug in a cold place.
b) Loss of water:

Loss of water from aqueous solution will give rise to concentration and possibly
crystallization of solute. e.g. Formation of crystals in the solution of calcium
gluconate injection.

ASIF HASAN NILOY

GB Pharm24 (3rd Semester)

Drug Stability 3

Evaporation of water from liquid and semi-solid (oil in water) emulsions may
cause cracking of these systems.

Efflorescent ( ) substances tend to lose water. The result will be decrease

in weight with a corresponding increase in potency of materials. E.g. Boras,
Caffeine, Sodium sulphate, Sodium carbonate etc.

Protection: Storage the products in well-closed containers.

c) Absorption of water:

Absorption of moisture from the atmosphere is a common cause of deterioration

of a variety of products. E.g. glycerin suppositories will absorb moisture and
became opaque while gelatin capsules will soften.

Some salts e.g. calcium chloride, potassium citrate, potassium hydroxide,

potassium carbonate are deliquescent. Their tendency to deliquescence will
depend upon the humidity and temperature of the atmosphere.

The hydroscopic materials absorb moisture from the atmosphere to cause

deterioration. E.g. Glycerin, H2SO4, dehydrated alcohol and most dry extracts.

Effervescent tablets and granules will react prematurely in a moist atmosphere.

Protection: Storage of all such materials in well-closed containers.

d) Crystal growth:

By falling in temperature, decrease the solubility of a solute and the

decomposition of crystals from aqueous solution occurs because the vehicle
becomes supersaturated with respect to the solute. e.g. Calcium gluconate
injection, 10% w/v

In suspensions, growth of the crystals is also undesirable. There is a tendency for

the crystals to bind together to form a hand cake, which is difficult to re disperse.

In topical and ophthalmic preparations large particle produce a gritty texture,

which is unacceptable for these preparations.

The cause of crystal growth in suspensions are summarized as follows: -

ASIF HASAN NILOY

GB Pharm24 (3rd Semester)

Drug Stability 4
(i)

Temperature fluctuation

(ii)

The presence of metastable form of crystals

(iii)

Presence of a small crystals

(iv)

Change of crystal structure.

Protection:
a. By avoiding the metastable form of drug.
b. Storing the drug in an environment, which exhibits the minimum temperature
fluctuation.
c. Increasing the viscosity of the suspending medium
d. A narrow size range of crystals should be used and incorporation of a surfaceactive agent which is absorbed on the crystal surfaces.
e) Polymorphic changes: Many substances exist as two or more crystalline forms are
said to be polymorphic upon storage in the dry state or in suspension. There is the
possibility of interconversion of these forms. Such changes may because alteration is
solubility and possibly crystal growth in aqueous suspension.
Protection: The formulated product should contain a stable crystalline form of the drug.
f) Color Changes:

A change in color of a pharmaceutical product is usually just a visual indication

that some form of chemical or photochemical decomposition is occurring.

Medicines are often colored for aesthetic reasons and color fading is a common
source of instability.

Certain water soluble dyes e.g. indigo carmine, tend to fade rapidly in the
presence of reducing substance such as lactose and dextrose.

Dyes also tend to fade when present in tablets exposed to light.

Protection:
a. Color change may be prevented by incorporating an ultraviolet light absorbing
compound in the tablet formulation.
b. By avoiding fading agent.

ASIF HASAN NILOY

GB Pharm24 (3rd Semester)

Drug Stability 5
g) Pressure: In certain drug, pressure causes degradation of the drug due to cracking of
the system. E.g. suppositories made of semi-solid materials are not too much resistant to
pressure. So, when pressure is applied it may be broken.
Protection: Controlled pressure and almost care should be taken when administered.
h) Contact: Drugs also may be deteriorated through physical contact among them e.g. Eutectic
mixture, Explosives.
Hydrolysis: Hydrolysis is considered to be the major causes of deterioration of drugs.
Especially for those in aqueous solution.
It may be defined as the reaction of a compound with water. Drugs containing as ester or
amide linkage are susceptible to hydrolysis. The main classes of drugs that are the esters,
amide and lactams. Hydrolysis is frequently catalyzed by hydrogen ions or by other
acidic or basic species that are commonly encountered as component of buffers.
Types: There are two types of hydrolysis.
1) Ionic Hydrolysis. Ex- Potassium acetate, Codeine Phosphate
2) Molecular Hydrolysis. Ex- Esters, Amides, Lactams
Examples of Esters, Amides and lactams
Ester Linkage Example

Amide Linkage Example

Lactam Linkage Example

Cocaine

Dibucaine

Nitrazepam

Physo stigmine

Lignocaine

Chlordiazepoxide

Tetracaine

Hydrochlorthiazide

Cephalasporins

Methyl dopate

Pilocarpine

Benzo diazepines

Methyl P-amino benzoate

Reserpine

Barbiturates

Procaine

Ergomeorine

Penicillin

Aspirin

Benzylpenicillin sodium

Atropine

Chloramphenicol

ASIF HASAN NILOY

GB Pharm24 (3rd Semester)

Drug Stability 6
Hydrolysis of Ester linkage drug (ASPIRIN): A drug may undergo several simultaneous
catalytic reactions all of which are hydrolytic in nature. A prime example of this
phenomenon is this decomposition of Aspirin into salicylic and acetic acids. Over the pH
range of 1 to 12 it has been predicted that six simultaneous reactions occur.

Hydrolysis

of

Lactam

linkage

drug

(PENECILLINS

and

CEPHALOSRINS):

The

decomposition of these compounds in aqueous solution is catalyzed by hydrogen ion,

solvent, hydroxide ion, sugar and many butter species.

ASIF HASAN NILOY

GB Pharm24 (3rd Semester)

Drug Stability 7
Causes of Hydrolysis:
1. Temperature

5. Degree of composition

2. pH

6. Presence of divalent metal

3. Light

7. Solution polarity and ionic strength

4. Solvent nature

8. High drug concentration

Protection of Hydrolysis: Degradation of drugs through hydrolysis can be protected by

the following way: 1. Prevention of contact between drug and water.
The obvious method of protection is to prevent contact between the material and water.
This method is concerned with protecting the dry material against water vapor and
involves control of atmospheric humidity during preparation, purification and packing
and satisfactory design of the final container.
2. Adjustment of pH.
Prevention of contact is impossible in liquid dosage forms that contain water. Many
hydrolytic reactions catalyzed by acid and bases, one method of achieving a reduction in
the rate of decomposition is by adjusting the pH to an optimum level on which the
catalytic effect is at a minimum.
Drug

Optimum pH

Atropine Sulphate

3.8

Procame

3.6

Benzocaine

4.9

Cincochaine

Aspirin

2.4

3. Choice of solvent.
Partial or full replacement of water with a solvent of lower dielectric constant generally
causes a considerable decrease in the velocity of ester hydrolysis.
Ex- ethanol, glycols, glucose and mannitol solutions and substituted amides. Barbiturate is
much stable in room temperature in propylene glycol water, then it water alone.

ASIF HASAN NILOY

GB Pharm24 (3rd Semester)

Drug Stability 8
4. Complexation.
Formation of molecular complexes between the hydrolysable substance and a second
component may inhibit hydrolysis.
Ex- Benzocaine is protected against hydrolysis by complexation with caffeine.
5. Surfactants.
Surfactants also may use to stabilize the drug.
Ex- The half-life of benzocaine was increase 18 times by the addition of Na-lauryl sulfate.
6. Modification of chemical structure.
If certain substances are added to the alkyl chain of aliphatic or aromatic esters or to the
benzene ring of aromatic esters causes a decrease in the hydrolytic rate.
Ex- by increasing the length of or by branching the acyl or alkyl chain, the rate of
hydrolysis of esters usually decrease, owing to steric hindrance.
7. Production of salts and esters.
A technique is employed to increase the stability of pharmaceuticals undergoing
degradation through ester hydrolysis is to reduce their solubility by forming less stable
salt of the drug.
Ex- insoluble procaine salts of benzyl penicillin has lower rate of decomposition.
8. Change of dosage form.
Hydrolysis of drug can often be reduced by changing the dosage form of the drug.
Antacid Suspension (less stable Tablet Antacid (More stable)
Oxidation: Oxidation of a compound can be defined as the removal of an
electropositive atom, radical or the addition of an electronegative atom or radical.
Oxidation often involves the addition of oxygen or removal of hydrogen.
Oxidation process may be completed by the following two ways: 1. Slowly under the influence of molecular oxygen, (auto oxidation) which involves
a free radical chain process.
2. The elimination of electron without the addition of oxygen.
e.g. ferrous ion oxidized to the ferric ion.
Fe++

Fe+++

ASIF HASAN NILOY

GB Pharm24 (3rd Semester)

Drug Stability 9
Examples: The drug which under oxidative degradation include
Phenolic compound such as morphine & Phenylephrine
Steroids
Antibiotics
Vitamins such as Vit-A
Fats
Fixed oils
Auto oxidation: Auto oxidation may defined as the reaction of any material with
molecular oxygen. It occurs spontaneously under normal condition and of then involves
free radicals.
Mechanism of Auto oxidation:

The mechanism is a chain reaction and involves the

following three steps.

(i)

Chain initiation

(ii)

Chain propagation

(iii)

Chain termination.

Chain inhibition: An organic compound (R H) is converted into an active free radical

(R0) during the initiation steps as a result of the influence of some factor such as heat,
light, presence of trace metals or other free radical.
RH

R0 + H

Chain propagation: This reaction is the chain reaction during which a free radical absorb
a molecule of oxygen to form a peroxy radical (R OO 0).
The peroxy radical then abstracts hydrogen from another molecule of RH to form a
hydroperoxide and a new free radical R0.
R will absorb a molecule of oxygen and thus continue the reaction.

The propagation step can continue until either all of the organic compound or the
oxygen has been consumed.

ASIF HASAN NILOY

GB Pharm24 (3rd Semester)

Drug Stability 10
Chain termination: it involves two steps
a) Self-termination: This involves reaction between two free radical and the
production of inactive (non free radical) product.

b) Chain breaking termination: This involves reaction between the free radicals and
compound that are known as chain inhibitors and result in the formation of stable
and comparatively unreactive free radicals.
R0 + IH RH + I0

Common Drugs that are reported to react with oxidation

Vitamin D

Sulfadiazine

Penicillin

Vitamin A

Apomorphine

Streptomycin

Vitamin E

Heparin

Tobramycin

Riboflovin

Morphine

Protection against Oxidation:

1. Presence of anti-oxidant
Oxidation may be reduced by the use of anti-oxidant a negative catalyst. They are very
effective in stabling pharmaceutical product undergoing a free radical mediated chain
reaction. These substances are easily oxidation potentials than the active ingredients.
Thus, they undergo preferential degradation or act as chain inhibitor of free radical by
providing an electron and receiving the excess energy possessed by the activated
molecules.
The ideal anti-oxidant has the following properties: 1) Effectiveness in low concentration.
2) Adequately soluble in the oxidizable product
3) Non toxic
4) Non irritant

ASIF HASAN NILOY

GB Pharm24 (3rd Semester)

Drug Stability 11
5) Odorless, Tasteless and should not impart color to the product.
6) Decomposition product should not be non-toxic and non-irritant.
7) Stable and effective over a long period of time.
8) Neutral and should not react chemically with other constituent present.
9) Non-volatile.
10) Thermo stable.
11) Compatible with container closure system.
Mode of action:
1. Primary antioxidants act by interfering with the propagation step of the autoxidation
process.
2. To maintain the propagation chain process free radical is require the antioxidant
molecule (AH) has the ability to react with such radicals & this results in the formation
of free radical A* which is not sufficiently reactive to sustain the chain process.
3. Finally, the antioxidant radical is annihilated by combination with another
antioxidant radical or some free radical.
Anti-oxidants

commonly

used

for

Anti-oxidants commonly used for oil

aqueous systems:

systems:

1. Sodium sulfate

1. Ascorbyl palmitate

2. Sodium metabisulfate

2. Hydroquinone

3. Sodium thiosulfate

3. Propyl gallate

4. Sulfur dioxide

4. Lecithin

5. Ascorbic acid

5.

- tocopherol

Synergists: Two or more anti-oxidants may be more effective than (would be expected
on the basis of)\ their individual activities. This is known as synergists and in general the
best mixtures are those that contain and initiation suppression and propagation
suppressions. Ex Ethylene diamine tetra-acetic acid (EDTA). It stabilize ascorbic acid,
penicillin.

ASIF HASAN NILOY

GB Pharm24 (3rd Semester)

Drug Stability 12
2. Presence of reducing agent
Oxidation of pharmaceutical preparation may be referred by the addition of a
reducing agent. Reducing agents are effective against oxidizing agent as well as
atmospheric oxygen. E.g. potassium and sodium metabisulphates, bi-sulphaties and
sulphites.
3. Adjustment of pH:
Many oxidative decomposition involving a reversible oxidation reduction process is
influenced by the hydrogen ion concentration.
Ex the decomposition of aqueous solution of ascorbic acid. pH of the system will
affect the stability of the preparation.
4. Removal of oxygen:
Oxidative decomposition of drug will depend on the contact of the drugs with
atmospheric oxygen. So the decomposition of the drugs may be minimized by
limiting contact of drug with atmospheric oxygen.
5. The presence of surface-active agent:
The oxidation of emulsified system can be removed by adding excess surface-active
agents.
Example Water insoluble oil methyl linoleate is a low rate of oxidation when
dispersed in water. When potassium laureate is added to this system, emulsions are
formed.
6. Presence of chelating agent:
Chelating agents tend to form complexes with the trace amounts of heavy metal ions
inactivating their catalytic activity in the oxidation of medicaments.
Examples EDTA, citric acid, tartaric acid.
Carboxylation: The absorption of CO2 from the atmosphere by a pharmaceutical product
is a more frequently occurrence than the loss of CO 2 by decarboxylation.
Example Solutions of KOH, NaOH, Ca(OH)2 & lead substance become turbid due to
the formation of insoluble carbonates.
2NaOH + CO2 Na2CO3 + H2O

ASIF HASAN NILOY

GB Pharm24 (3rd Semester)

Drug Stability 13
Decarboxylation: Decarboxylation means the elimination of CO2 from a compound
containing carboxyl group (-COOH) and thus becomes inactivated.
Example This is most commonly encountered when parenteral solution of sodiumbicarbonate are autoclaved.
Solution of NaHCO3 Decarboxylation

Isomerization: isomerization means the conversion of an active drug to a less active or

inactive isomers having the same structural formula but differs in sterio-chemical
configuration.
Polymerization: It involves the combination of two or more identical molecule to form a
much larger and more complex molecule.
Ex polymerization is the prime cause of degradation of the antiseptic formaldehyde.
OHCH2OH + nHOCH2OH + HOCH2OH

HOCH (OCH ) OCH OH

2

2 n

Photochemical degradation: Photochemical degradation means decomposition of

compounds of pharmaceutical product or drug resulting from the absorption of radiant
energy in the form of light.
By exposure to light at particular wavelengths the following degradative reactions occur:
(i)

Oxidation-reduction

(ii)

Ring arrangement

(iii)

Modification

(iv)

Polymerization

Protection against photochemical degradation: The photochemical degradation of a

sensitive material can be reduced by protecting it from light.
This may be activated by the following ways
1. Storing the product in a clear glass container and then either placing it in the dark
or enclosing it in an opaque wrapper. It is suitable for parental solution.
2. Light resistant container may be used. A light resistant as one that does nor
transmit more than 15% of incident radiation between 290 and 450nm.

ASIF HASAN NILOY

GB Pharm24 (3rd Semester)

Drug Stability 14
3. Colored glass containers are most commonly used. Yellow green or amber glasses
are satisfactory since they transmit very little below 400nm.
4. Riboflavin is protected by a stabilizer which has a hydroxyl group attached to or
near the aromatic ring.
5. The photodegradation of sulphacetamide solutions may be inhibited by an
antioxidant such as Na-thiosulphate or metabisulphite.
What is AST? Define AST condition.
AST: Various tests have introduced that involve storage of product under conditions
which accelerate decomposition such testing method are referred to as AST. That means
Accelerated Stability Test.
AST Conditions: Accelerating conditions are those, which affect the drug in storage life.
These conditions are given below
(1) Temperature
(2) Light
(3) Humidity or Moisture
(4) Pressure etc.
Types of AST: Mainly there are three types of AST. Those are
(i) Accelerated testes for chemical stability
(ii) Accelerated testes for photochemical stability
(iii) Accelerated testes for physical stability
There are also three types of accelerated testes for physical stability, those are
(i) Accelerated testes for moisture Absorption
(ii) Accelerated testes for Emulsion stability
(iii) Accelerated testes for suspension stability
Accelerated testes for chemical stability: When determining the chemical stability of a
pharmaceutical product it is essential that the assay employed should be sufficiently
specific to distinguish between the drug and its decomposition products. For example,
the allopurinol preparation is acceptable until the drug content is 90% of the initial
concentration. The first order rate equation shows that the shelf-life will be 150 days.

ASIF HASAN NILOY

GB Pharm24 (3rd Semester)

Drug Stability 15
Limitations of accelerated storage testes for chemical stability: 1. The predicted shelf life of a preparation will only be valid if the accelerated test is
carried out or the final packaged product. Ex. The use of on air tight container will
reduce the rate of oxidation in a drug.
2. It is not possible to extend the prediction to all climatic conditions, especially
those encountered in tropical regions where there are large diurnal variations in
temperature.
3. The accelerated technique can only applied to those forms of decomposition
which increase with rise in temperature. For example, it is possible for the zeroorder decomposition of a drug in suspension to become first order at higher
temperature because of complete solution of the drug in the vehicle.
4. When the decomposition process is complex, it could result in an inaccurate
prediction of shelf-life.
5. The elevated temperature may induce a decomposition process that is not
normally significant at ambient temperatures. This is true of autocatalytic reactions
which are accelerated by the products of decomposition.
6. The shelf-life prediction only applies to the product formulation investigated one
cannot expect the prediction to be valid for different formulations of the same
drug.
Accelerated test for physical stability: As result of the many and varied causes of physical
instability in pharmaceutical products it is not possible to devise a single universal test
that will accelerate the breakdown of all preparations.
The AST for physical stability will be applied to assess stability towards.
(a) Moisture
(b) Emulsions
(c) Suspension etc.
***Objective of AST: The objective of AST are as follows: (I) Selection of the best formulation
(II) Preparation of Shelf-life
(III) Determination of toxicity or safety level.

ASIF HASAN NILOY

GB Pharm24 (3rd Semester)

Drug Stability 16
(i) Selection of the best formulation: It involves the rapid detection in different initial formulation of the same product. The
best formulation from a series of possible choice is the one that exhibits the least amount
of decomposition in a given time under the influence of a reasonably high stress.
(ii) Prediction of Shelf-life: Shelf life is the time period during which the dosage form is supposed to retains its
original qualities. The various steps involved in the prediction of shelf-life are as follows:
1) The preparation for which the stability is to be determined is divided into different
portions and each portion is stored at different elevated temperatures such as 40, 50, 60
and 70 in order to accelerate the degradation.
2) Samples from each portion are withdrawn at various intervals of time and the
remaining concentration of the active ingredient is measured.
3) The order of reaction is determined by a suitable method such as graphical method
which involves plotting of appropriate function of the concentration against time to
obtain a linear relationship. Other methods such as half-life method can also be used.
4) From the slopes of the lines, the reaction rate constant k for the degradation at each
of the elevated temperatures is calculated.
5) Employing the Arrhenius relationship, the reaction rate constant k for the degradation
at room temperature is determined. This may obtained from the linear plot of the
logarithm of the k values at various elevated temperatures against the reciprocal of
absolute temperatures and then extrapolating the curve to 25 and reading of the k
value at 25.
6) The k value obtained for 25 is then substituted in the appropriate rate equation and
an estimate is obtained for the shelf-life of the product i.e., for the time period during the
shelf-life period to assure 100% conc. In the product during use within the shelf life.
(iii) Prediction of safety level:The objective is to check a product after a given time to observe its amount of value that
fall below an acceptable limit of the decomposition after that time under high stress.
Determination extent of deterioration in product and hence to determine the toxicity
level.

ASIF HASAN NILOY

GB Pharm24 (3rd Semester)

Drug Stability 17
Limitation of AST:
1) AST is not suitable in all climatic conditions; especially they are encountered in
tropical regions where there are large diurnal variations in temperature.
2) The AST can be applied to those, which forms the decomposition. Decomposition
increases with the rise of temperature.
3) In all AST there is the possibility that the applications of high stresses may cause
reactions that could not take place under the lower stresses associated with
normal storage conditions.
4) The decomposition type reaction and the order of reaction may change under
accelerated temperature.
5) When the decomposition process is complex involving a series of simultaneous at
consecutive reaction, storage of the product at elevated temperature may produce
a change in the relative contributions of the component reaction.
6) The prediction shelf-life of a preparation will only be valid if the accelerated test is
carried out on the final packaged product.
7) AST does not predict the expiry date.
8) AST does not show what the types of degraded products are and also not show
where the degraded products are toxic or safe.
9) The decomposition causes by AST is not differential with the decomposition
caused by heating effect of light.
10) The test can be performed only under high stress conditions.
11) Under the accelerated condition of temperature disturbance happens with relation
humidity. Because at elevated temperature the humidity will be lower than that in
the room. So loss of H2O from the products may occur and the decomposition
may be unexpected.

ASIF HASAN NILOY

GB Pharm24 (3rd Semester)