PHARMACEUTICS-IB (PHYSICAL

PHARMACY) [Theory]
Credit Hours: 03 (2nd Semester)
Lecture : 06
(Kinetics)

Hussain Ali (PhD)

27th March 2019
 Drug Stability
• Drug stability means 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.

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 Criteria For Acceptable Levels of Stability
Type of Stability Conditions maintained throughout the shelf life of the drug
product
Chemical Each active ingredient retains its chemical integrity and labeled
potency within the specified limits.

Physical The original physical properties, including appearance,

palatability, uniformity, dissolution, & suspendability are
retained.

Microbiologic Sterility or resistance to microbial growth is retained according

to the specified requirements. Antimicrobial agents retain
effectiveness within specified limits.

Therapeutic The therapeutic effect remains unchanged.

Toxicologic No significant increase in toxicity occurs.

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 Importance of Degradation Kinetics
 Development of optimum formulation (preformulation
studies)

 Determine the optimum storage conditions (temperature,

light, humidity)

 Selecting the proper container for dispensing (glass or

plastic, clear or opaque, cap liners)

 Predicting the shelf life of the drug

 Anticipating drug excipient interactions.

 Stabilization of the drugs against degradation

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 Importance of Degradation Kinetics
• Degradative reactions in pharmaceutical formulations
take place at definite rates & are chemical in nature.

• Degradation kinetics aims to predict the intrinsic

stability of a drug in order to anticipate problems that
may arise during development

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 Kinetics
Motion or
Kinetics
movement

Velocity, rate or
rate of change

Kinetics deals with the study of the rate at which processes

occur and mechanism of chemical reactions

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 Outline:
Kinetics
Reaction Rates How we measure rates.

How the rate depends on

Rate Laws amounts of reactants.

How to calc amount left or time

Integrated Rate Laws to reach a given amount.

Half-life How long it takes to react 50%

of reactants.

How rate constant changes with

Arrhenius Equation T.

Link between rate and molecular

Mechanisms scale processes.
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 processes

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 WHY DO WE STUDY ABOUT KINETICS?

It gives an in light into the mechanism of changes involved

Allows a prediction of the degree of change that will occur

after a given time has elapsed.

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 Rates of Reaction
An important part of studying
chemical reactions is to monitor the
speed at which they occur. Chemists
look at how quickly, or slowly,
reactions take place and how these
rates of reaction are affected by
different factors.

The light produced by a firefly depends

on the speed of a particular chemical
reaction that occurs in its abdomen.
,
Rate & Order of reaction

• According to the law of mass action:

• The rate of a chemical reaction is proportional to the product of molar
concentrations of the reactants each raised to a power equal to the
number of molecules of the substance undergoing reaction.
• aA + bB + ….. Product

• The velocity at which a reactant or a product undergoes chemical change is

called the rate of a reaction. The rate, velocity or speed of a reaction is
given by the expression

where dc is increase or decrease of concentration over a time interval dt.

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 Order of Reaction
• The order of reaction is defined as the manner
in which the rate of a reaction varies with the
concentration of reactants. The overall order
is the sum of the exponents of concentration
terms that afford a linear plot.
• For above reaction, order of reaction = a + b

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 Chemical Reaction Rates
• Chemical kinetics is the study of the rate at which
chemical reactions occur.

The term reaction rate, or rate of reaction refers to:

• the speed that a chemical reaction occurs at, or

• the change in amount of reactants consumed or
• products formed over a specific time interval

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Chemical kinetics
Chemical kinetics is the study of the rates and the mechanism of
chemical reactions. Commonly the measure of how fast the
products are formed and the reactants consumed is given by the
rate values.

The study of chemical kinetics has been highly useful in

determining the factors that influence the rate, maximum yield
and conversion in industrial processes. The mechanism or the
sequence of steps by which the reaction occurs can be known. It
is also useful in selecting the optimum conditions for maximum
rate and yield of the chemical process.
The rate of a reaction tells us how fast the reaction occurs. Let us consider
a simple reaction.
A+B→C+D
As the reaction proceeds, the concentration of the reactant A and B
decreases with time and the concentration of the products C + D increase
with time simultaneously. The rate of the reaction is defined as the change
in the concentration of any reactant or product in the reaction per unit
time.
For the above reaction,
Rate of the reaction
= Rate of
disappearance of A
= Rate of
disappearance of B
= Rate of appearance
of C
Types of Rates
 Initial Rates
◦ Rates measured at the beginning of the
reaction, which is dependent on the initial
concentrations of reactants.
 Instantaneous Rates
◦ Rates measured at any point during the
reaction.
 Average Rates
◦ An overall rate measured over a period or time
interval.
 During the reaction, a change in the concentration is infinitesimally small
even for small changes in time when considered in seconds. Therefore
differential form of rate expression is adopted. The negative sign shows the
concentration decrease trend and the positive sign shows the concentration
increase trend.
 Units of Rate

 Reaction rate has units of concentration divided by time.

 Zero order k = Msec-1

 1st order k = sec-1

 2nd order k = M-1sec-1

 Mole / litre sec or mol 1-1s

 Mole / litre min or mol 1-1 min-1

 Mole / litre hour mol 1-1 h-1


Factors influencing reaction rates
There are number of factors which influence the rate of the
reaction.
These are :
(i) Nature of the reactants and products concentration
(ii) Concentration of the reacting species
(iii) Temperature of the system
(iv) Presence of catalyst
(v) Surface area of reactants
(vi) Exposure to radiation
(i) Effect of nature of the reactant and product
Each reactant reacts with its own rate. Changing the
chemical nature of any reacting species will change the rate
of the reaction.
(ii) Concentration of the reacting species
As the initial concentration of the reactants increase in the
reaction mixture, the number of reacting
molecules Since
increase. will the reaction occurs when
chemical reacting species the together and
come
collisions close
are more frequent when
collide,the
the concentrations
are higher. This effect increases the reaction rate.
(iii) Effect of temperature
Increase in temperature of the system increases the rate of the reaction. This
is because, as the temperature increases the kinetic energy of the molecules
increases, which increases the number of collisions between the molecules.
Therefore the overall rate of the reaction increases.

(iv) Effect of presence of catalyst

A catalyst is a substance that alters the rate of a chemical reaction, while
concentration of catalyst remaining the same before and after the reaction.
The addition of catalyst generally increases the rate of the reaction at a given
temperature. Also, catalyst is specific for a given reaction.
(v) Effect of surface area of reactants
As the particle size decreases surface area increases for the same mass. More
number of molecules at the surface will be exposed to the reaction conditions such
that the rate of the reaction increases. Thus the reactants in the powdered form (or)
in smaller particles react rapidly than when present in larger particles.

(vi) Effect of radiation

Rates of certain reactions are increased by absorption of photons of energy. Such
reactions are known as photochemical reactions. For example, H2 and Cl2 react
only in the presence of light. With increase in the intensity of the light (or)
radiation, the product yield increases. For photosynthesis light radiation is essential
and the process does not proceed in the absence of light.
 Order of Reaction
• Zero order reaction

• First order reaction

• Second order reaction

• Pseudo order reaction Pseudo zero order reaction

Pseudo first order reaction

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 Zero order reaction

• The rate of the reaction doesn't depend on concentration of the

reagent(s).
• The rate expression for chemical reaction,
A B

• Rate of reaction = - d[C]/dt = K

OR

where, [C] indicates decreasing concentration of reagent & k indicates

rate constant.

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 Zero order reaction
• Integrating of rate equation between initial
concentration A0 at t = 0 & At, concentration
after t = t we obtain,

OR

OR

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• The initial concentration corresponding to Co is ordinarily
written as ‘a’ & concentration remaining at time ‘t’ as ‘x’.
When this linear equation is plotted with x on vertical axis
against t on horizontal axis, the slope of the line is equal to
– k.

Slope = – k
Concentration

Time
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 Zero – Order Reactions
The half life of a drug in a formulation is the time required
for the amount (conc.) of the drug to drop to half its
original value.

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Zero – Order Reactions

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 First order reaction

• Rate of the reaction depends on concentration of any

one reagent.
• The rate expression for chemical reaction,

A B

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The rate law for the first
order reaction is:

Integrating the equation

Converting to common
log to the base 10 we
get:
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• The initial concentration corresponding to Co is
ordinarily written as ‘a’ & concentration
remaining at time ‘t’ as ‘x’. When this linear
equation is plotted with ‘log Ct’ on vertical axis
against ‘t’ on horizontal axis, the slope of the line
is equal to
log Ct Slope = – kt/2.303

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Time
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Example: A solution of a drug contained 500
units/mL when prepared. It was analyzed after
40 days and was found to contain 300 units/mL.
Assuming the decomposition is first order, at
what time will the drug have decomposed to
one-half of its original concentration?

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 Second order reaction
• The rate of the reaction depends upon concentration of two
reactants.
• There are two cases,
• Case 1: when the initial concentrations of A & B are identical
or two molecules of the same reactant are involved in the
reaction.
A+B products or
2A products

• Where, a = initial concentration of the reactant or reactants

and x = concentration of the reactant changed in time t. 36
Integrating rate equation between initial concentration ‘a’ at t = 0 &
(a-x), concentration after t = t, we obtain,

• Case 2: When the initial concentrations of the two reactants are

different, i.e.,
A+B products
• Assume the initial concentration of two reactants to be a & b

• Integrating above equation,

• (a - x) and (b - x) are the concentrations of A and B after time

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interval, t.
 Pseudo order 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.

These may occur under the following conditions:

• One or more of the reactants enters into the rate
equation in great excess compared to others;
• One of the reactant is catalyst;
• One or more of the reactants is constantly replenished
during the course of reaction
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Degradation pathways

Hydrolysis

Oxidation-Reduction

Photolysis

Racemization

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 Hydrolysis
• Many pharmaceuticals contain ester or amide
functional groups, which may undergo hydrolysis
in solution.

• Examples of drugs that tend to undergo hydrolytic

cleavage of an ester or amide linkage are
anesthetics, antibiotics, vitamins, & barbiturates.

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 1. Ester hydrolysis

• The hydrolysis of an ester into a mixture of an acid &

alcohol essentially involves the rupture of a covalent
linkage between a carbon atom & an oxygen atom.
• The alkaline hydrolysis of an ester is irreversible where as
acid hydrolysis of an ester is reversible.
• The general form of the kinetic equations to express acid
or base-catalyzed hydrolysis is as follows:

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• This is done by keeping the OH- or H- at a
considerably higher concentration than the ester
concentration or by keeping constant through the use
of buffers. This would cause the previous equation
reduce to:

• Whenever possible, first order kinetics expression

have been employed in the study of the degradation
of drugs by ester hydrolysis, but at times, second
order kinetics expression have been employed.
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 2. Amide hydrolysis
• Amides are relatively stable than esters.

• Pharmaceuticals such as niacinamide,

phenethicillin, barbiturates, & chloramphenicol
degrade by amide hydrolysis.

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 3. Ring alteration
• A hydrolytic reaction can proceed as a result of ring
cleavage with subsequent attack by hydrogen or
hydroxyl ion.

• Its examples are hydrochlorothiazide, pilocarpine &

reserpine. Quite often equilibrium kinetics is
associated with such mechanisms.

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 Oxidation–reduction
• The oxidative decomposition of pharmaceutical compounds is
responsible for the instability of preparations such as steroids,
vitamins, antibiotics, & epinephrine

• These reactions are mediated either by free radicals or by molecular

oxygen.

• Autoxidation is most common form of oxidative decomposition of

pharmaceuticals, which involves a free radical chain process.
A:B A*+ B*

• These radicals are highly unsaturated & readily take electrons from
other substances, causing oxidation.
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 Functional group susceptible to oxidation
Functional Group Drugs/Excipients

Aldehydes Paraldehyde

Amines Clozapine

Carboxylic acids Fatty acids

Conjugated dienes Vitamin A

Ethers Diethyl ether

Nitrites Amyl nitrite

Phenols Catecholamine, Morphine

Thioethers Cholpromazine

Thiols dimercaprol
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 photolysis
• Photolytic degradation (as it applies to pharmaceutical stability)
is the degradation that results from exposure to ultraviolet or
visible light in the wavelength range of approximately 300–800
nm.
• Photo degradation rates are therefore directly dependent on
the amount of incident radiation and on the amount of
radiation that is absorbed by the compound or the formulation.
• It is important to remember that a compound may undergo
photolytic degradation even if it does not itself absorb radiation
in the UVA or visible region.

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o If the molecules absorbing the radiation take part themselves in the
main reaction, the reaction is said to be photochemical.

o Where the absorbing molecules do not themselves participate directly

in the reaction, but pass on their energy to other molecules that do,
the absorbing substance is said to be a photosensitizer.

o The photodegradation of chlorpromazine through a semiquinone free-

radical intermediate follows zero order kinetics.

o Alcoholic solutions of hydrocortisone, prednisolone, &

methylprednisolone degrade by reactions following first-order
kinetics.

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 Racemization

 An optically active substance loses its optical

activity without changing its chemical composition

 In general, undergo degradation in accordance with

first order kinetic principles

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 Shelf life
• It can be defined as the period of time during which a pharmaceutical
product, if stored correctly, is expected to comply with the specification
as determined by stability studies on a number of batches of the
product.

• The shelf life is used to establish the expiry date of a batch. The shelf-
life is the time required for 10% of the material to disappear; it is the
time at which concentration has decreased to 90% of its original
concentration.

Zero order

First order 50
Arrhenius Equation
• Arrhenius observed that most reaction rates
depend on the following three factors
A. Fraction of molecules possessing energy of
activation (Ea) or greater
B. number of collisions per second
C. fraction of molecules having the correct orientation
• Arrhenius noted that the increase in reaction rate is
not linear with increase in temperature in most
reactions.
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• Svante August Arrhenius (1859–1927) developed
a mathematical relationship between k (the rate
constant) and Ea (energy of activation).

Slope = – Ea/R

In k
(slope-intercept form)
1/T

• Therefore, if k is determined experimentally at

several temperatures, and ln k vs 1/T is plotted Ea
can be calculated from the slope of the plot. 52
Where, k2 & k1 are rate constants at
temperature T2 & T1 respectively. Slope = – Ea/R

The results of Arrhenius analysis can be

useful in predicting the impact of

In k
changes in storage conditions or
climatic zone on expiration dating
interval of a given drug-product.

In practice, multiple levels of thermal

stress are applied to the formulation so
that appropriate shelf-life estimates 1/T
can be made for normally expected
marketing conditions.
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 ICH Recommended Evaluation

• The shelf life of a commercial drug product must be

determined in the commercial container closure at
the defined storage conditions.
• ICH requires at least 12 months stability data at the
time of NDA submission.
• Most products require at least 24 months to be
commercially viable.
• The ICH Q1E recommended how the 12 months data
may be used to predict long-term stability.

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 Collision Theory
• Two species can only react if they come into
contact with each other.
• The species have to collide and then they may
react.
Why may ?
• Because they have to:
• collide the right way around
• and they have to collide for enough energy for the
old bonds to break.
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 Collision Theory
• Appropriate orientation:
Consider a simple reaction involving a collision between
two molecules: ethene, CH2=CH2 and hydrogen chloride,
HCl, for example. These react to give chloroethane.

CH2=CH2 + HCl CH3CH2Cl

• As a result of the collision between the two molecules,

the double bond between the two carbons is converted
into a single bond. A hydrogen atom gets attached to one
of the carbons and a chlorine atom to the other.
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 Accelerated Stability Testing:
• Accelerated stability protocols have been developed to
reduce the time required to determine the products shelf
life at the storage conditions.
• The accelerated stability protocols depends on
• calculating the rate constant of the degradation reactions
at elevated temperature (by plotting some function of
concentration vs. time) and then plotting the log k vs.
• 1/T(in Kelvin).

• The rate at room temperature or storage temperature is

then obtained by extrapolating the straight line.

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 Accelerated Stability Testing:
Limitations of accelerated stability testing based on elevated
temperatures:
– Suitable only if the reaction rate is a thermal phenomenon
– Not suitable if the degradation depends on diffusion or is a
photochemical reaction
– Not suitable if the degradation is caused by freezing, microbial
growth or excessive shaking.
– Can not be used for products containing suspending or
thickening agents that coagulate on heating (Methyl Cellulose).
– Not suitable for ointments and suppositories that melt at
elevated temperature.
– Some emulsions have higher stability at elevated
temperatures.
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