DRUG STABILITY

Types of stability studies:

• Physical
• Chemical
• Microbiological
 Factors affecting Stability
1- Environmental factors
- Temperature - Light
- Oxygen - Moisture
- Carbon dioxide

2- Drugs or excipients in the dosage form

- Particle size of drug
- pH of the vehicle

3- Microbial contamination
4- Trace metal Contamination
5- Leaching from containers
 Physical stability
• Physical stability implies that:
- The formulation is totally unchanged throughout its shelf
life and has not suffered any changes by way of
appearance, organoleptic properties, hardness,
brittleness, particle size etc.

- It is significant as it affects:
• pharmaceutical elegance
• drug content uniformity
• drug release rate.
 Physical stability

Formulation Likely physical instability Effects

problems

Oral solutions 1- Loss of flavour Change in

2- Change in taste smell or feel
3- Presence of off flavours or taste
due to interaction with plastic
bottle
4- Loss of dye (discoloration)
5- Precipitation
 Physical stability
Formulation Likely physical instability Effects
problems
Parenteral 1. Discoloration due to photo Change in
chemical reaction or oxidation appearance
solutions and in bio-
2. Presence of precipitate due to
interaction with container or availability
stopper
3. Clouds due to:
(i) Chemical changes
(ii) The original preparation of a
supersaturated solution
 Physical stability
Formulation Likely physical Effects
instability problems

Suspensions 1- settling 1-Loss of drug

2- caking content uniformity
3- crystal growth in different doses
from the bottle

2- loss of elegance.
 Physical stability
Formulation Likely physical Effects
instability problems
Emulsions 1- Creaming 1- Loss of drug
2- Coalescence content uniformity
in different doses
from the bottle

2- loss of elegance
Physical stability

Coalescence
 Physical stability
Formulation Likely physical Effects
instability problems
Semisolids 1. Changes in: 1-Loss of drug
(Ointments a) Particle size content uniformity
and b) Consistency
suppositories) 2- loss of elegance
2. Caking or
coalescence 3-change in drug
release rate.
 Physical stability
Formulation Likely physical instability Effects
problems
Tablets Change in: Change in
a) Disintegration time drug release
b) Dissolution profile
c) Hardness
d) Appearance (soft or
become very hard)
 Physical stability

Formulation Likely physical instability Effects

problems
Capsules Change in: Change in
a) Appearance drug release
b) Dissolution
c) Strength
 Chemical stability:
• Chemical stability implies:
The lack of any decomposition in the chemical moiety that is
incorporated in the formulation as the drug, preservatives or
any other excipients.

This decomposition may influence the physical and chemical

stability of the drug
 Pathways of Drug Degradation
• A number of drug substances and excipients
employed in pharmaceutical products have a variety
of chemical structures, which may be broken down
under certain environmental conditions.
• Major degradation routes are,
➢ Hydrolysis
➢ Oxidation
➢ Photolysis
 Hydrolysis
• Drugs susceptible to hydrolytic
degradation
• If the drug is a derivative of carboxylic
acid or contains functional groups
based on this moiety, for example an
ester, amide, lactone, lactam, imide or
carbamate, then we are dealing with a
drug which is liable to undergo
hydrolytic degradation.

Examples of chemical groups susceptible to hydrolysis

• Drugs that contain ester linkages include acetylsalicylic acid
(aspirin), physostigmine, methyldopate, tetracaine and procaine.
Ester hydrolysis is usually a bimolecular reaction involving acyl–
oxygen cleavage.
• The hydrolysis of amides involves the cleavage of the amide linkage
as for example, in the breakdown of the local anaesthetic
cinchocaine. This type of link is also found in drugs such as
chloramphenicol, ergometrine and benzylpenicillin sodium.

Hydrolysis of the ester group of procaine.

Hydrolysis of the amide linkage of cinchocaine.

 Hydrolysis
• Examples of lactam ring hydrolysis include
decomposition of nitrazepam and
chlordiazepoxide.
• Other drugs susceptible to hydrolysis include
the penicillins and cephalosporins.
 Controlling drug hydrolysis in solution
• Optimization of formulation
• Hydrolysis is frequently catalyzed by hydrogen ions (specific
acid-catalysis) or hydroxyl ions (specific base-catalysis) and
also by other acidic or basic species that are commonly
encountered as components of buffers. This latter type of
catalysis is referred to as general acid–base catalysis.
• Several methods are available to stabilize a solution of a drug
which is susceptible to acid–base catalyzed hydrolysis.
• The usual method is to determine the pH of maximum
stability from kinetic experiments at a range of pH values and
to formulate the product at this pH.
• Alteration of the dielectric constant by the addition of
nonaqueous solvents such as alcohol, glycerin or propylene
glycol may in many cases reduce hydrolysis.
 Controlling drug hydrolysis in solution
• Since only that portion of the drug which is in solution will
be hydrolyzed, it is possible to suppress degradation by
making the drug less soluble.
Eg. The stability of penicillin in procaine–penicillin suspensions
was significantly increased by reducing its solubility by
using additives such as citrates, dextrose, sorbitol and
gluconate.
• Adding a compound that forms a complex with the drug
can increase stability.
Eg. The addition of caffeine to aqueous solutions of
benzocaine, procaine and tetracaine was shown to
decrease the base-catalysed hydrolysis of these local
anaesthetics in this way.
• Solubilisation of a drug by surfactants protects against
hydrolysis.
 Oxidation
• After hydrolysis, oxidation is the next most
common pathway for drug breakdown.
• In cases where simultaneous hydrolytic and
oxidative degradation can occur, the oxidative
process has usually been eliminated by
storage under anaerobic conditions without
an investigation of the oxidative mechanism.
 Oxidation processes
• Oxidation involves the removal of an electropositive atom, radical
or electron, or the addition of an electronegative atom.
• Oxidative degradation can occur by autoxidation, in which reaction
is uncatalysed and proceeds quite slowly under the influence of
molecular oxygen, or may involve chain processes consisting of
three concurrent reactions – initiation, propagation and
termination.
• Initiation can be via free radicals formed from organic compounds
by the action of light, heat or transition metals such as copper and
iron which are present in trace amounts in almost every buffer.
• The propagation stage of the reaction involves the combination of
molecular oxygen with the free radical R‹ to form a peroxy radical
ROO‹, which then removes H from a molecule of the organic
compound to form a hydroperoxide, ROOH, and in so doing creates
a new free radical.
 Oxidation processes
• The reaction proceeds until the free radicals are destroyed
by inhibitors or by side-reactions which eventually break
the chain.
• The rancid odour which is a characteristic of oxidized fats
and oils is due to aldehydes, ketones and shortchain fatty
acids which are the breakdown products of the
hydroperoxides.
• Peroxides (ROOR,) and hydroperoxides (ROOH) are
photolabile, breaking down to hydroxyl (HO‹) and or alkoxyl
(RO‹) radicals, which are themselves highly oxidizing
species.
• The presence of residual peroxides in polyoxyethylene
glycols (PEGs) is a cause for concern when these excipients
are used in formulation, as for example in the case of
fenprostalene.
Simplified oxidation scheme involving a chain process
 Drugs susceptible to oxidation
• Steroids and sterols represent an important class of
drugs that are subject to oxidative degradation through
the possession of carbon– carbon double bonds
(alkene moieties) to which peroxyl radicals can readily
add.
• Polyunsaturated fatty acids, commonly used in drug
formulations, are particularly susceptible to oxidation.
• For drugs, such as the cholesterol-lowering agent
simvastatin, that contain conjugated double bonds,
addition of peroxy radicals may lead to the formation
of polymeric peroxides (simvastatin polymerises up to
a pentamer), cleavage of which produces epoxides
which may further degrade into aldehydes or ketones.
 Drugs susceptible to oxidation
• Polyene antibiotics, such as amphotericin B which contains
seven conjugated double bonds (heptaene moiety), are
subject to attack by peroxyl radicals, leading to aggregation
and loss of activity.
• The oxidation of phenothiazines to the sulfoxide involves
two single-electron transfer reactions involving a radical
cation intermediate. The sulfoxide is subsequently formed
by reaction of the cation with water.
• The ether group in drugs such as econazole nitrate and
miconazole nitrate is susceptible to oxidation. The process
involves removal of hydrogen from the C–H bonds in the α-
position to the oxygen to produce radicals, which further
degrade to α-hydroperoxides and eventually to aldehydes,
ketones, alcohols and carboxylic acids.
 Stabilization against oxidation
• Antioxidants
• It is very difficult to remove all of the oxygen from a
container and even traces of oxygen are sufficient to
initiate the oxidation chain.
• The propagation of the chain reaction may be
prevented or delayed by adding low concentrations of
compounds that act as inhibitors.
• Such compounds are called antioxidants and interrupt
the propagation by interaction with the free radical.
• The antioxidant free radical so formed is not
sufficiently reactive to maintain the chain reaction and
is eventually annihilated.
 Stabilization against oxidation
• Reducing agents such as sodium metabisulfite
may also be added to formulations to prevent
oxidation.
• These compounds are more readily oxidized
than the drug and so protect it from oxidation.
• Oxidation is catalyzed by unprotonated
amines such as aminophylline, and hence
admixture of susceptible drugs with such
compounds should be avoided.
• Cis–trans isomerisation may be a cause of loss of potency of a drug
if the two geometric isomers have different therapeutic activities.
Vitamin A (all-trans-retinol) is enzymatically oxidised to the
aldehyde and then isomerised to yield 11-cis-retinal, which has a
decreased activity compared with the all-trans molecule.
 Photochemical decomposition
• Many pharmaceutical compounds, including the
phenothiazine tranquillizers, hydrocortisone, prednisolone,
riboflavin, ascorbic acid and folic acid, degrade when
exposed to light.
• As a result there will be a loss of potency of the drug, often
accompanied by changes in the appearance of the product,
such as discoloration or formation of a precipitate.
• Photodecomposition might occur not only during storage
but also during use of the product.
• For example, sunlight is able to penetrate the skin to a
sufficient depth to cause photodegradation of drugs
circulating in the surface capillaries or in the eyes of
patients receiving the drug.
 Photochemical decomposition
• Primary photochemical reaction occurs when the wavelength of the
incident light is within the wavelength range of absorption of the
drug (usually within the ultraviolet range, unless the drug is
coloured), so that the drug molecule itself absorbs radiation and
degrades.
• Photodegradation may also occur with drugs that do not directly
absorb the incident radiation, as a consequence of absorption of
radiation by excipients in the formulation (photosensitisers) which
transfer the absorbed energy to the drug, causing it to degrade.
• In assessing the photostability of a product it is therefore necessary
to consider the final formulation rather than simply the drug itself.
• The rate of the photodegradation is dependent on the rate at which
light is absorbed by the system and also the efficiency of the
photochemical process.
• The effect of ultraviolet light on chlorpromazine (CLP).
• The first step of the photodegradation is the loss of an electron to
yield the semiquinone free radical R. Further stages in the
degradation yield the phenazathonium ion P, which is thought to
react with water to yield chlorpromazine sulfoxide (CPO). The
chlorpromazine sulfoxide is itself photolabile and further
decomposition occurs. Other products of the photooxidation include
chlorpromazine N-oxide and hydroxychlorpromazine.
 Photochemical decomposition
• In formulations that contain low drug concentrations, the
primary photochemical reaction follows first-order kinetics;
the kinetics are more complicated at higher concentrations
and in the solid state because most of the light is then
absorbed near the surface of the product.
• Although it is difficult to predict which drugs are likely to be
prone to photodegradation, there are certain chemical
functions that are expected to introduce photoreactivity,
including carbonyl, nitroaromatic and N-oxide functions,
aryl halides, alkenes, polyenes and sulfides.
• The mechanisms of photodegradation are of such
complexity as to have been fully elucidated in only a few
cases.
• examples – chlorpromazine and ketoprofen.
Stabilization against photochemical decomposition

• Pharmaceutical products can be adequately protected from

photo-induced decomposition by the use of colored glass
containers and storage in the dark.
• Amber glass excludes light of wavelength <470 nm and so
affords considerable protection of compounds sensitive to
ultraviolet light.
• Coating tablets with a polymer film containing ultraviolet
absorbers has been suggested as an additional method for
protection from light.
• In this respect, a film coating of vinyl acetate containing
oxybenzone as an ultraviolet absorber has been shown to
be effective in minimizing the discoloration and photolytic
degradation of sulfasomidine tablets.
 Polymerization
• Polymerisation is the process by which two or more
identical drug molecules combine together to form a
complex molecule.
• It has been demonstrated that a polymerisation process
occurs during the storage of concentrated aqueous
solutions of aminopenicillins, such as ampicillin sodium.
• The reactive β- lactam bond of the ampicillin molecule is
opened by reaction with the side-chain of a second
ampicillin molecule and a dimer is formed. The process can
continue to form higher polymers.
• Such polymeric substances have been shown to be highly
antigenic in animals and they are considered to play a part
in eliciting pencilloyl specific allergic reactions to ampicillin
in humans.
 Polymerization
• The dimerising tendency of the aminopenicillins
increases with the increase in the basicity of the side-
chain group, the order, in terms of increasing rates,
being cyclacillin << ampicillin < epicillin < amoxycillin.
• The hydrate of formaldehyde, HOCH2OH, may under
certain conditions polymerize in aqueous solution to
form paraformaldehyde, HOCH2(OCH2)nOCH2OH, which
appears as a white deposit in the solution. The
polymerization may be prevented by adding to the
solution 10–15% of methanol.
Kinetics of Drug Decomposition
 Kinetics of Drug Degradation
• When developing final dosage form, it is important to know
whether the product is safe for its intended therapeutic use
over a long period of storage time.
• Compounds used in the final product as well as active
ingredients should be stable at normal environmental
conditions.
• If the ingredients undergo chemical degradation, one
should know the pathway of degradation, the byproducts,
and their safety to the recipients.
• In addition, administered drugs undergo biotransformation
in biological fluids and body organs.
• Therefore, kinetic analysis of the degradation and
biotransformation of chemical compounds is important.
 Kinetics
Irreversible Reactions
• Zero-Order Reactions
• First-Order Reactions
• Apparent Zero-Order Reactions
• Second-Order Reactions
Determination of the Order of Reaction and Its Rate Constant
• Differentiation Method
• Integration Method
Other Irreversible Reactions
• Autocatalytic Reactions
• Parallel Reactions
• Consecutive Reactions
Reversible Reactions
• Reversible First-Order Reactions
• Reversible Second-Order Reactions
• Reversible and Series Reactions (Eigenvalue Method)
Enzyme–Substrate Reactions
• Enzyme–Substrate Reactions without Inhibition
• Enzyme–Substrate Reaction with Inhibition
Acid–Base Catalyzed Degradation Kinetics
• Acid–Base Catalyzed Hydrolysis of Neutral Chemicals
• Acid–Base Catalyzed Hydrolysis of Polyprotic Weak
Acids and Weak Bases
Degradation Kinetics in Inclusion Complexes, Micelles,
and Liposomes
Temperature Effects on the Reaction Rate Constants
 Single and Multiple Reactions, Elementary
Reactions, Molecularity, and Order of Reactions
• Consider whether a reaction takes place via a
single stoichiometric equation that has a single
rate expression (i.e., single reaction) or whether
more than one stoichiometric equation must be
used to express the rate of reaction of all the
reaction constituents (i.e., multiple reactions).
• Consider the following reaction with
stoichiometric equation:
• A+B→P
• The rate of the reaction (rate of disappearance of
reactants A and B or rate of production of
product P) is proportional to the concentration of
the reactants in the mixture.
• The rate equation for this stoichiometric reaction
is:
• Rate = k [A][B]
• where k is the rate constant and the square
brackets in Equation indicate the concentrations
of each reactant. The reaction is called an
elementary reaction.
 Molecularity
• The molecularity of a single elementary reaction
is the number of molecules engaged in the
reaction.
• A simple elementary reaction is referred to as
uni-, bi-, or termolecular if one, two, or three
chemical species are involved in the chemical
reaction, respectively:
• A → B + C (Unimolecular)
• A + B → C + D (Bimolecular)
• A + 2B → C + D (Termolecular)
 Rate of a chemical reaction
• According to the law of mass action,
• the rate of a chemical reaction is proportional to the product of the molar
concentration of the reactants each raised to a power usually equal to the
number of molecules, a and b, of the substances A and B, respectively,
undergoing reaction.
Classifying reactions: the order of reaction

• Reactions are classified according to number of

reacting species whose concentration determines
the rate at which the reaction occurs, i.e. the
order of reaction.
• For zero-order reactions, the breakdown rate is
independent of the concentration of any of the
reactants;
• First-order reactions, the reaction rate is
determined by one concentration term,
• Second order reactions, the rate is determined by
the concentrations of two reacting species.
 Order of Reaction
• For a general single elementary reaction
• αA + βB+ γC + ⋅⋅⋅⋅ → ωX + σY + τZ + ⋅⋅⋅⋅

• Rate of the reaction is expressed as:

 Order of Reaction
• The exponents are determined experimentally
• The reaction is of the ath order with respect to
reactant A, bth order with respect to reactant
B and so on.
• The total order of the reaction is to the nth in
Equation
 Order of Reaction
• Regardless of the order of the reactions, the
rate of reaction has the units of
concentration/time (i.e., mole/L sec).
• The units of the rate constant are dependent
on the overall order of the reaction:
• k = (concentration)1−n (time)−1
 Irreversible reactions
• Zero-Order Reactions:
• In this type of reaction the decomposition proceeds at a
constant rate and is independent of the concentrations of
any of the reactants.
• In a zero-order reaction [i.e., n = 0], the rate of an
elementary unimolecular reaction is expressed as:

• where ko is the zero-order rate constant and t is the time.

The rate of reaction is independent of the concentration of
the reactants and constant. Integrating Equation yields:
 Zero-Order Reactions
• The half-life (t0.5) and shelf-life (t0.9) are
defined as the times required for the
concentration of the drug to decrease by 50
and 10%, respectively.
• For zero-order reactions,
 Zero-Order Reactions
• The half-life of a zero-order reaction is directly
proportional to [A]o.
• Unlike other reaction kinetics, it is possible to
determine the time required for 100% of the
drug in a formulation to completely
decompose.
• It takes two half-lives for complete
degradation for zero-order reactions.
 Zero-Order Reactions
• Degradation of vitamin A acetate to
anhydrovitamin A.

Degradation of vitamin A acetate in ethanol/water (95%/5%)

 First-Order Reactions
• The rate of the first-order degradation kinetics
(A B) is written as

• where k1 is the first-order rate constant.

 First-Order Reactions

• Degradation of gemcitabine HCl at pH 3.2 at different

temperatures
 First-Order Reactions
• A plot of the logarithm of the fraction
remaining as a function of time gives a
straight line with a slope of −k1
• The first-order rate constant, k1, has the units
of time–1.
 First-Order Reactions
• The half-life and shelf-life for first-order
reactions are given by
 First-Order Reactions
• The half-life and the shelf life are constant and
independent of the drug concentration, [A]o.
• For example, if the half-life of a first-order
reaction is 124 days, it takes 124 days for a drug
to decompose to 0.5 [A]o.
• Also it takes another 124 days for 50% of the
remaining 50% of the drug to decompose.
• The time required for 100% degradation cannot
be calculated because ln ([A]/[A]o) is an indefinite
number.
• First-order plot for hydrolysis of homatropine in hydrochloric acid (0.226
mol/lit) at 90°C
 Apparent Zero-Order Reactions
• Not many zero-order degradation reactions exist in
pharmaceutics.
• Some drugs in certain common dosage forms, such as
suspensions, follow zero-order kinetics.
• Looking at the phase where the degradation takes place,
first-order degradation kinetics is observed.
• But the overall degradation kinetics in the entire dosage
form is a zero-order rate.
• Drug degradation kinetics in an aqueous phase of a
suspension dosage form is expressed as:
 Apparent Zero-Order Reactions
• In suspension formulations, the concentration
of the drug in the aqueous phase remains
constant (i.e., saturated) until the suspended
drug particles are completely exhausted:

• where k1 [A]s is the solubility of a drug.

Hydrolysis of aspirin in an aqueous suspension at 34°C.

 Second-Order Reactions
• There are two types of second-order reactions

• For type I second–order reactions, the rate of

reaction is given by:

• where k2 is the second-order rate constant.

Integration of Equation yields
 Second-Order Reactions
• The half-life of a second-order reaction is
given by:

• The half-life of a second-order reaction is

inversely proportional to [A]o.
 Second-Order Reactions
• For type II second-order reactions, the rate can be
expressed as:

• At time t, the amounts of A and B reacted are equal

(i.e., stoichiometrically 1:1 ratio and [A]o XA = [B]o XB
where XA and XB are the fractional conversions of A and
B, respectively).
• Equation can then be written in terms of XA as:
 Second-Order Reactions

• If the initial concentrations of A and B are the

same, this Equation is same as Equation for
type I.
• For type I, the plot of 1/[A] vs. t gives a
straight line with a slope of k2.
The linear plot of the
concentration, ln([B]/[A])
vs. time t, for second-
order reactions.
 Determination of the Order of Reaction
and Rate Constant
• The methods used to determine the order of
the reaction and its rate constant may be
divided into two groups:
1. Differentiation method
2. Integration method
 Differentiation Method
• In the differentiation method, the rate of degradation with
respect to time is calculated from the experimental data for
concentration vs. time.
• Two techniques of the differentiation method are the
complete experimental run and the initial rate run.
• The analysis of the single experimental run plots the
concentration vs. time followed by smoothing of the data
via regression analysis.
• From the regressed curve, one determines the slope at
suitable time values, which gives the rate (i.e., −d[A]/dt).
• For a single reaction, the general form of the rate
expression is given by:
 Differentiation Method

• The rate constant k and the order of reaction can

be determined from the plot of log (−d[A] /dt) vs.
log [A].
• First, the rate is determined from the
concentration vs. time curve.
• Second, the rate vs. concentration is plotted in a
log–log plot.
• The slope and the y intercept furnish the order of
reaction and the rate constant, respectively.
Differentiation Method
Differentiation Method
 Differentiation Method
• The log–log plot of rate vs. mean concentration is
presented. The slope of this plot is 0.92, which is rounded
off to 1.0 (first-order).
• The intercept of the plot is −2.23, which gives k = 5.9 ×10−3
/ hr

Log−log plot of rate vs. mean concentration

 Differentiation Method
• Another technique of the differentiation method
is the initial rate measurement.
• A series of experiments are carried out for
different initial concentrations over a short time
period (5 to 10% or less conversion).
• Each rate measurement requires a new
experiment with a different initial concentration.
• The initial rate of the reaction is determined from
the curve of the concentration vs. time.
• The log of the initial rate is then plotted against
the log of the initial concentration.
 Differentiation Method
• Method of initial rate measurement for
determining the order of reaction
 Integration Method
• The integration method is based on
comparisons between the observed
experimental data (concentration vs. time)
and the calculated values of the analytical
equations.
• The equations are obtained from the
integration of the mathematical expressions of
the rate of the reaction.
 Integration Method

• If Equation 1 or Equation 2 fits the experimental

data, the calculated values of the rate constant at
various time intervals should all be the same or
have small variations without any definite trend.
 Integration Method
• Plot the experimental data according to
Equation 1 and Equation 2,
• ln[A] vs. t
• 1/[A] vs. t.
• Figure shows that Equation 2 fits the
experimental data well.
• The slope of this straight line gives the value
of k2
 Integration Method
• Comparative results of general integration method for
first-order and second order reactions:
• (a) first-order plot and (b) second-order plot
 Temperature Effects on
Reaction Rate Constants

• The degradation of final dosage forms will

occur over a long time at low temperature
(i.e., 25°C).
• For example, it may take a year or more even
for 5 to 10% of drugs to decompose. When
one considers the errors in analytical assays,
the degradation data may not be significant.
 Temperature Effects on
Reaction Rate Constants
• To obtain degradation data within a reasonably short
period of time, degradation experiments are carried
out at higher temperatures.
• Then, the kinetic data at high temperatures are
extrapolated to the corresponding kinetic data at 25°C.
• However, it is imperative to know the dependence of a
degradation reaction on temperature.
• Two theories that describe the temperature
dependence of the rate equation are: collision theory
and transition-state theory.
 The collision theory
• In a gas, molecules A are moving and colliding together
with molecules B. The total number of collisions of
molecules A with molecules B, ZAB, at a given time, Δt, is,

• where nA and nB are the numbers of moles of the molecules

A and B in a unit volume, respectively,
• MA and MB are the molecular weights of the molecules A
and B, respectively, and
• σAB is the mean collision diameter [= ½ (σA + σB)], where σA
and σB are the diameters of molecules A and B,
respectively.
 The collision theory
• However, not every collision between molecules A and
B leads to a reaction.
• Only a small fraction of the collisions leads to a
reaction as a result of those molecules possessing
energy in excess of the minimum energy, E.
• The collisions are then equal to the Boltzman factor
(e−E/RT ), and the actual number of collisions for a given
reaction is:
 The collision theory
• The rate for a bimolecular reaction is given as:

• Equation shows that the rate constant is

dependent on the temperature
 The transition-state theory
• Molecules colliding or possessing sufficient energy can
combine to form unstable intermediates, known as
activated complexes.
• These activated complexes transiently exist and are
spontaneously converted to products in a first-order rate
process.
• They are also constantly in equilibrium with the reactants.
Thus, reactions can be written

where (AB)* is the transient activated complex.

 The transition-state theory
• The rate equations are:

• where K*AB is the equilibrium constant.

• The rate of spontaneous decomposition of the activated complex
for the specific rate of any reaction and given as:

• where h is the Planck constant and k is the Boltzman constant

 The transition-state theory

• The thermodynamic relationship between the

standard free energy change and the equilibrium
constant of the activated complex is given as:
 The transition-state theory

• The term eΔS*/R in Equation is less sensitive to the

temperature effects than the terms kT/h and e−ΔH* /RT.
• Thus, the rate constant k is
 The transition-state theory

• The enthalpy of activation is directly related to

the Arrhenius activation energy

• The difference between E and ΔH* is very small,

and ΔH* is replaced by E.
• Thus, Equation approximates to:
 The transition-state theory
• The transition-state theory assumes that the rate
of formation of a transition state intermediate is
very fast and the decomposition of the unstable
intermediate is slow and is the rate-determining
step.
• On the other hand, the collision theory states
that the rate of the reaction is controlled by
collisions among the reactants.
• The rate of formation of the intermediate is very
slow and is followed by the rapid decomposition
of the intermediates into products.
 The transition-state theory
• Based on these two theories, the following expression can be
derived to account for the temperature dependence of the
rate constant:

• where ko*, T, E, and R are the proportionality constant, the

absolute temperature, the activation energy, and the gas
constant, respectively.
• Schematic diagram of the transition state for an exothermic reaction
 The transition-state theory
• For most chemical reactions, E >> mRT, and
Equation then becomes

• where A is called the frequency factor. This

Equation is known as Arrhenius’ law.
• It was originally suggested by Arrhenius to fit
chemical reaction experiments over a wide range
of reaction temperatures.
 The transition-state theory
• A plot of lnk as a function of the reciprocal
temperature gives a straight line with a slope of
−E/R, from which E can be calculated.
• Another way to determine the activation energy
is using two different values of k (k1 and k2) at
two different temperatures (T1 and T2):
• Arrhenius plot for the degradation of gemcitabine at pH 3.2
Storage
Rate constant for degradation
temperature
(month-1)
(°C)
25 0.03
30 0.045
40 0.09
 •Answer the following questions related to stability of omeprazole.

Time (days) Percentage drug remaining

Room temperature Accelerated stability testing
(25°C) (40°C)
0 100 100
7 86 83
14 78 73
21 71 65
28 64 57

Table 1: Stability of omeprazole stored at different temperature conditions.

•Based on the chemical structure of omeprazole, what could be the likely degradation pathway? [1 mark]
•Using data provided in Table 1, calculate the order of the degradation reaction at both temperature conditions. [1 mark]
•Using data provided in Table 1, calculate rate constant (k) for degradation at both temperature conditions. [1 mark]
•Calculate the shelf-life of omeprazole when stored at 25°C and 40°C. [2 marks]
•Calculate the increase in shelf-life of omeprazole when stored at 5°C instead of 25°C. [5 marks]