UNIT-V

DRUG STABILITY
 Definition
kinetics & Drug stability
• Drugs stability is defined as the pharmaceutical dosages form to
maintain the physical, chemical, therapeutic and microbial properties
during the time of storage and uses by the patient.
• Stability is defined as the capacity of a drugs substance to remain
within the established specification to maintain its identity, strength,
quality and purity throughout the retest or expiration during period.
• Chemical kinetics is the study of rate of chemical changes taking
place during chemical reaction.
• As applied to pharmaceutical formulation , this include a study of
physical and chemical changes in drugs and dosage form, factor
influencing the rate of these chemical reaction, accelerated stability
testing and prediction of shelf life.
Introduction
Reaction kinetics/ Chemical kinetics

Is the branch of Physical Chemistry which deals with the rate

of reaction including rate laws, external factors such as
temperature, time, pressure, concentration, characteristics
and also includes mechanism of the reaction or sequence of
steps involved.
Law of mass action:
• Given by Norwegian Chemist Guldberg and Wage.

• It states that for any given reaction the rate is directly

proportional to molar concentration of the reacting species
when the temperature condition is kept fixed.

A+B C+D

Rate of reaction ∝ Concentration of reactants

R = K [A]m [B]n
RATES AND ORDER OF
REACTION
• The velocity with which a reaction or a process occurs is called as its
rate, concentration of drugs influences the rate of reaction or process
is called as the order of reaction or order of process.
Consider the following chemical reaction
Drug A Drug B

• The rate of forward reaction is expressed as :

-dA/dt
• -ve sign = concentration of drugs A decreases with time.
• As the reaction proceeds, the concentration of the drugs B increases
and the rate of reaction can also be expressed as:
dB/dt
• Experimentally, the rate of reaction is determined by measuring the
decrease in concentration of drugs A with time.
• If c is the concentration of drug A, the rate of decrease in c of drug A
as it is changed to B can be described by expression as function of
time t.
dC/dt = -kc
Where,
k= rate constant

• The order of a reaction determines the way in which the

concentration of a reactant or reactants influences the rate of a
chemical reaction.

• N2 + 3H2 2NH3
• Dx/dt= -d[N2]/dt = -1/3 d[H2]/dt =1/2 d[NH3]/dt
Factor affecting rate of reaction
• Concentration (Order of reaction)
• Nature of reactant
• Temperature
• Catalyst
• Surface area of reactant

How concentration Of reactant effect rate of reaction.

Rate of reaction ∝ Concentration of reactants (Theoretically)
Rate of reaction ∝ [Concentration]n
order of reaction (can only be find out by experiments)

R=K[Conc]n
N= Integer, fraction
K= Rate constant/velocity constant/ specific rate constant
Oder of reaction do not have any relation with stoichiometric coefficient of
nay reaction.
Order of Reaction:

• It is defined as the sum of the powers of the concentration of reactants in the given
rate law.

• aA + bB --- ab [AB]

• Rate of reaction ∝ [A]m [B]n (calculate by experiment)

• R= K [A]m [B]n

• K=R/[A]m [B]n

• K= (Mol/lt)1-n time-1 (unit)

• Thus order of reaction is m + n

• Range of the order of reaction varies from 0 to 3.

Eg: Rate = K [N2O5] Order is 1

Rate = K [H2] [O2] Order is 2

Rate = K [H2] [NO2]2 Order is 3

Factor affecting rate of reaction
2. Nature of reactant
Phase (Solid, Liquid, Gas)
Homogeneous rxn fast then heterogeneous.
Chemical nature (inversely proportional to chemical stability)

3. Surface area of reactant

More the surface area of reactant more the interaction more will be the rate
of reaction.

4. Catalyst
Down the activation of energy (barrier of energy reactant have to cross to
convert into product).

5.Temperature
Increase in temp rate of reaction increases (Arrhenius)
K= Ae-(Ea/RT)
Molecularity of the reaction:
• The molecularity of a reaction refers to the numbers of reacting
species (molecules, atoms, or ions) participating in an elementary
(Simple, Single step, non complex) chemical reaction which collide
simultaneously. (collision theory)

• If only one type of molecules undergoes a change in to yield the

product , the product is said to be unimolecular.

Eg: (Decomposition of products)

NH4NO2 N2 + 2H2O (Single step elementary rxn)

Molecularity of the reaction:

• If two molecules undergoes to change yield the product, the reaction is said to be
bimolecular.

• 2HI H 2 + I2

• Reaction that involves more than one steps ( complex reaction) may have different
molecularity and order of reaction.

• Molecularity cannot ne more than 3

• It cannot be zero

• It cannot be fraction.

• We can theoretically calculate the molecularity

Molecularity of the reaction:

• They are classified as:

a) Elementary reaction

b) Complex reaction

• They are also classified as:

a) Unimolecular

b) Bimolecular

c) Trimolecular
 ON
Pseudo-order reaction

TI
EAC
OFR Zero order reaction
ER

First order reaction

RD
O

Second order reaction

OF
ES
T YP

Third order reaction

 Pseudo-order reaction
Are the reactions in which one of the reacting species is
in excess showing the order different from the actual
order.

CH3COOC2H5 + H2O  CH3COOH + C2H5OH

• Original order of the reaction is 2

• But actual order is 1

Pseudo Zero order reaction:

Is a reaction which may be a first order, but behaves like a zero

order reaction depending on the experimental conditions.

Eg: drug degradation in suspension

Pseudo First order reaction:

Is a reaction which may be a second order, but behaves like a first

order reaction depending on the experimental conditions.

Eg: acid hydrolysis of methyl acetate

 Zero order reaction
• It is defined as a reaction in which the rate does not depend on the
concentration terms of the reactants.
• Its is also called as constant rate process.

• Mathematically expressed as:

• Where ko is the specific rate constant for zero order

• Unit of zero order reaction is moles/litre. Sec.

• Eg: Colourloss of liquid multisulfonamide preparation, oxidation of

vitamin A in oily solution.
Half life of zero order
reaction:

• It is the time required for the concentration of the reactant

to reduce to half of its initial concentration in a reaction.

c = a/2 at t = t ½

• Unit is sec/conc. or min/conc. or hour/conc.

t 1/2
Shelf life of zero order
reaction:

• It is defined as the time required for the concentration of the

reactant to reduce 90% of its initial conc.

c = 90a/100 at t = t 90

• Unit is sec/conc. or min/conc. or hour/conc.

t 90
 First order reaction
• It is defined as the reaction in which the rate of reaction depends on
the conc. of one reactant.

• Mathematically expressed as:

• Where k1 is the specific rate constant for first order

• Unit of first order reaction min-1 or hour-1 or sec-1.

• Eg: Acid hydrolysis of ester, inversion of sugar, disintegration of

radioactive elements.
Half life of first order reaction:

t 1/2

Shelf life of first order reaction:

t 90
Second Order Reaction
• It is defined as the reaction in which the rate of reaction depends
on the conc. of two reactants.

• Eg: A + B  Products

• The rate equation can be written as:

[A]1 [B]2

• Unit of second order rate constant is litre/ mole /min

• Eg: alkaline hydrolysis of esters such as methylacetate or

ethylacetate, hydrolysis of chlorbutanol in presence of NaOH
• Half life of second order reaction:

t 1/2

• Shelf life of second order reaction:

t 90%
Determination of order of
reaction

•Graphical method
•Substitution method
•Half life method
Graphical method
• Most reliable method of determination of order of reaction.

• A straight line that gives better fit is identified.

 Substitution method
• Data is substituted in the integral equations of zero, first and
second order reactions to get k value and the one that gives
constant k value is identified.

ORDER OF REACTION INTEGRAL EQUATION

Zero order reaction k

First order reaction k1 log

Second order reaction k2 = .

 Half life method
• The average k value is calculated and then t1/2 values are
calculated.

ORDER OF REACTION INTEGRAL EQUATION

Zero order reaction t1/2

First order reaction t1/2

Second order reaction t1/2 =

 Physical and
Chemical Factors
Influencing
Degradation of
Pharmaceutical
Products
 Internal factors External factors
Solvent Temperature

pH Light (photochemical)

Buffer Oxygen

Ionic strength Moisture

Dielectric constant Radiation

Excipients
Influence of solvent
• The more polar solvent (nitrobenzene & ethanol) accelerate
the formation of more polar products or retards the
formation of less polar products.

• Less polar solvent (hexane) accelerates the formation of less

polar products or retards the formation of more polar
products.
 Influence of pH
• Most of the drugs degrade at extreme pHs. ie. At high H+ and OH-
because they are the catalytic species and accelerate the rate of
reaction.

• Ionic species degrade at a faster rate than the neutral/ unionized

species because the ionic species are more water soluble & prone
to chemical reaction.

• The optimum pH for maximum stability is 3.5 to 5.0

 Influence of Buffers
• The vehicle of dosage form is adjusted to defined pH using
buffers – which resist the changes in pH of the solution.

• Eg. of buffers are acetate, citrate, lactate, phosphate and

ascorbate.

• Buffers participate in the formation or breakdown of activated

complexes.

• The catalytic species are referred as General acid base catalysts

and Specific acid base catalysts.
General acid-base catalysts:

It refers to any acid or base we add to the solution will affect the
rate of reaction.

Specific acid-base catalysts:

It refers to the fact that just one acid or base from the solvent
(specifically H+ or OH- ions) will affect the rate of reaction.
 Influence of Ionic strength

• Drug degradation involves drug-ion or ion-ion species

interaction.

• The rate is affected by presence of other ions (sodium chloride)

in solution, but in presence of buffers the effect of ions is
nullified.

• As ionic strength increases, the rate of reaction between ions of

opposite charges decreases, whereas between ions of similar
charges increases.
Influence of dielectric constant

• The rate constant depends on the dielectric constant of the

solvent.
 Influence of excipients
• Excipients may act directly or indirectly in drug degradation.

• Direct – by acting as reactant or as catalyst.

• Indirect – moisture present in excipients accelerates the drug

degradation by changing melting behaviour or pH or functional
groups.

• Eg: Mg stearate accelerates discolouration of tablets containing

amines and lactose, sugars enhance hydrolytic degradation of
thiamine hydrochloride.
Influence of
temperature
• The rate of reaction increases about 2 or 3 times with every
10° rise in temperature.

• Arrhenius equation explains the effect of temperature on

k = Ae
the rate of reaction.

–Ea/RT
Taking log on both sides,
ln k = ln A – Ea/ RT ln e

Converting to log base 10

log k = log A -
• Energy of activation (Ea)- is the minimum energy that
the molecule should possess so that molecular
collisions produce the product.

• Arrhenius factor (A)- is the frequency of collisions

between the reacting molecules in a reaction.
Mechanism: Collision theory postulates

1) Collisions must occur between reactant molecules for the

reaction to proceed.

2) The colliding molecules must possess certain energy for

reaction to take place.

At any temperature molecules possess certain energy, but as

temp. rises more molecules absorb energy and get activated
which results in increased rate of reaction.
 Influence of light
• Drugs undergoing light induced chemical degradation is called
Photolabile (photosensitive) drugs.

• The light induced chemical degradation – Photolytic degradation

• The energy unit of radiation is photon.

• Photon is directly proportional to frequency or inversely

proportional to wavelength of the radiation.
• Photodegradation is usually hydrolysis and oxidation.

• Photodegrdation is mediated by free radicals to produce

dark or light coloured products.

• Eg: Riboflavin, ciprofloxacin, chlorpromazine, tetracycline.

Photolytic degradation may induce following changes:

• Degradation of substance
• Retention or transfer of energy
• Conversion to heat
• Emission of light at a new wavelength
Prevention of photolytic degradation:

• It can be inhibited with additives like antioxidants which interrupt

degradation processes. e.g: derivatives of aniline.

• It can be inhibited by using UV absorbers which capture the

photon and convert it to heat in case creams, ointments & liquid
d.f eg: hydroxy-substituted benzophenones.
• It can be prevented by use of opacifying and coating agents
in various dosage forms. e.g.. of opacifiers are yellow, red &
black iron oxides & e.g.. of coating agents includes film
coating, use of opaque blisters and capsules.
• Protection of drug from light can be achieved by the use of an

opaque or amber coloured container.

• The pharmacopoeia prescribe conditions for containers (eg: light

resistant) and storage (eg: protected from light) for

photosensitive drugs and formulations.

• Complex formation between photosensitive drug and
complexing agent is a method of stabilization of drugs. Eg:
caffeine as complexing agent for photostabilization of drug
riboflavin.
Influence of oxygen
• Chemical degradation under the influence of oxygen is called
Photo-oxidation.

• Oxidation is loss of electrons from a molecule.

• The reaction between compounds and molecular oxygen is

called auto-oxidation which proceeds in presence of O2, light
and traces of heavy metals.

• Eg: Riboflavin, morphine, prednisolone, epinephrine, arachis oil,

clove oil, ascorbic acid.
OXIDATION OF ASCORBIC ACID
General principles:
• Atmospheric oxygen promotes the rate of oxidation.

• Light provides the necessary energy to initiate the oxidation

process.

• The presence of trace heavy metals also accelerate the rate of

oxidation.

• Organic peroxides also promote the oxidation reaction.

• Oxidation reaction between ionic species proceeds faster compared

to neutral molecules.

• Oxidation reactions are catalysed by H+ and OH- ions. The hydroxyl

ions catalyse oxidation faster than hydrogen ions.
 Protection against Oxidation

• Antioxidants – eg. tocopherols, BHA, BHT, ascorbic acid.

• Chelating agents – eg. EDTA, citric and tartaric acid.

• Vehicles – replacing water with other solvents taking into

consideration solubility, ionic strength, polarity and dielectric
constant of the solvent.

• Micellar solubilization –surfactants protect the drug above its

CMC by entrapping drugs into micelles.
• Buffers – will impart stability to drug when oxidation is
catalyzed by H+ or OH- ions.

• Environmental control measures:

 Preventing the exposure to light – amber coloured containers or
secondary packaging.
Oxygen free environment – replacing air with inert gases such as
Nitrogen or CO2.
Low temperature storage – store the product in a cool place.
 Influence of moisture
• Water is a critical reactant and degradation catalyzed by moisture
is called hydrolysis.

• Mechanism of hydrolysis:
• Acts as a reactant or as a catalyst (H+ or OH- ions).
• Hydration
• Isomerization
• Alters the physical state by adsorbing on the surface of the
solid
• Solubilizing the drugs in the solvent
 • Eg. of drugs which decompose by hydrolytic pathway are esters
like Aspirin, Procaine, atropine and amides like
Chloramphenicol, ampicillin, cephalosporins, barbituric acid.

• Drugs with ester and amide groups react with one

molecules of water and undergo hydrolysis.
• Esters undergo hydrolysis to give acids and alcohols.
• Esters undergo hydrolysis at a faster rate than amides.
Hydrolysis of Aspirin:
Protection against
Hydrolysis
a) Buffers: are added to maintain the optimum pH to 3.5-5.
Eg: Pilocarpine is highly active at alkaline pH so acidic buffer
(boric acid buffer) is selected for maximum stability.

b) Complexation: Hydrolysis can also be inhibited by

addition of complexing agent. Eg: Hydrolysis of benzocaine
can be inhibited by addition of caffeine as complexing agent.
c) Suppression of solubility: when the solubility of drug decreases
the rate of hydrolysis is reduced because conc. of drug in solution
phase will be decreased.

Solubility can be suppressed by:

• Addition of additives like citrates, dextrose, sorbitol and
gluconates.
• Using salt form of drug which is poorly soluble eg: procaine
penicillin.
• Using poorly water soluble derivatives like esters of drugs
(chloramphenicol palmitate)
d) Removal of water

Avoid contact of drug with water by storing the drug in dry

form and when desired reconstitute the product. Eg.:
Streptomycin dry powder for injection or by using water
immiscible vehicle for the dispersion of drug eg. Aspirin in
silicone fluid.
Accelerated
Stability
studies
 Introducti
on
Stability of a pharmaceutical preparation is the capability of a
formulation in a specific container-closure system to remain
within its physical, chemical, microbiological, therapeutic and
toxicological specifications throughout its shelf life.

Stability testing is used to:

 Provide evidence as to how the quality of the drug product varies with
time.
 Establish shelf life for the drug product.
 Determine recommended storage conditions.
 Determine container closure system suitability.
ICH Guidelines
 Accelerated Stability Studies

 The Objective of Accelerated Stability study is to predict the shelf

life of the product, by accelerating the rate of decomposition,
preferably by increasing the temperature of reaction conditions.

 Preparations are subjected to high stresses during stability

testing.

 Common high stresses includes Temperature, humidity and

light.
Arrhenius equation

•It explains the effect of temperature on rate of a reaction.

According to Arrhenius, for every 10° rise in temperature, the
speed of reaction increases about 2-3 times.

•k = A e -Ea / RT
 Estimation of k value

• The reaction is conducted at several temperatures.

Concentration of reactants is determined.
• Appropriate graphs are drawn for the kinetic data. Data is
processed for all the orders and the order of the reaction
is identified.

• From the slopes of the lines, k values are calculated for all
temperatures.
Estimation of energy of activation

• Activation energy is the minimum energy that a

molecule should possess so that the molecular
collisions produce the product.
• A graph can be drawn by taking log k on y-axis
and reciprocal temperature (1/T) on x-axis.

• A straight line is obtained, the slope of the line is

negative and the magnitude is Ea / 2.303 R.

• The intercept corresponds to log A

• All the constants in the Arrhenius equation can be

obtained from the graph.
 Steps involved in prediction of
shelf life
• The Preparation is stored at different elevated temperatures, to
accelerate the degradation.

• Samples are withdrawn at different time intervals and the Order

of the reaction is determined.

• The graph permits the estimation of k value from the

slope. Similarly graphs are drawn for different elevated
temperatures and K value for each temperature are
• By using Arrhenius relationship, Log k
values are plotted against reciprocal of
absolute temperature, energy of
activation is calculated.
• Extrapolate the straight line to room
temperature (k25) or refrigerated
temperature and read the log k value on y-
axis.
• Substitute the k value in the appropriate
equation to get the shelf life of the
product by using shelf life eqn. for
respective order.
 Addition of Overages

• Excess amount of the drug can be added to the preparation to

maintain 100% of the labelled amount during the shelf life of the
product.

• Overages are calculated from the accelerated stability studies.

• A 10% decomposition is permitted during shelf life and thus 10%

of the drug is therefore added during manufacture.