Drug stability III

Chemical kinetics and Shelf life

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 Learning outcomes
• How the basic principles of chemical kinetics
can be applied to the study of stability of drug

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 Importance of studying kinetics of
drugs
• Provides evidence of the changing quality of
the drug substance or product with time
under the influence of temperature, light and
humidity
• Proposes to establish test period for the drug
and shelf life
• Recommend storage conditions

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 Rate, order, molecularity of reactions
• The speed of a reaction over time is called the rate of that
reaction
• Consider the following reaction

• The rate of the reaction (rate of disappearance of reactants A

and B or rate of production of product P) is directly 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 indicate the
molar concentrations of each reactant.

4
• The molecularity defines 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
• Unimolecular Reactions
– Molecularity is one, i.e., one type of molecules stoichiometrically
participated in the reaction
– Eg: Br2 2 Br
» Conversion of all trans – vitamin A to all cis – vitamin A
• Bimolecular Reactions
– Molecularity is two, i.e., two types of molecules are stoichiometrically
involved in the reaction
– H2 + I2  2HI
• Termolecular Reactions
—Reactions of termolecular and other higher molecularity are seldom observed
—This is because 3 or more molecules having sufficient kinetic energy must meet
simultaneously in the same region of space to yield a product
—Rare 5
• The sum of the concentration terms is called the order a reaction

• The number of concentration terms on which rate of a reaction

depends when determined experimentally.
• Usually in Pharmaceutics we have
– Zero
– Apparent or Pseudo zero
– First
– Second
– Third

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 Why does same reaction have
different molecularity& order
a) One of the reactant may present in large
excess
b) If one of the reactant is acting as a catalyst
c) When a reaction has several steps,it is possible
that one of the steps proceeds slower than
rest.

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 Important Concepts
• Rate constants
– All reactions have specific rate constants for a reactions that
change if the conditions of the reaction are changed
• Half-life
– The time required for half of the drug to disappear. [A]
becomes 0.5 [A]
• Shelf life
– Time required for 10% of the API to disappear. [A] = 0.9[A]
– It is also the time period during which the drug product is
expected to remain within the approved specification for user,
provided it is stored under recommended conditions
• Expiration date
– Date placed on the container designating the time prior to
which a batch of the product is expected to remain within its
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approved specifications provided it is stored under its defined
9
 Zero-order reactions
• The rate does not depend on the concentration terms of reactants
• - dA/dt = k0
– k0 is the specific rate constant for a zero order
• Eg:
– Colour – loss of liquid multi sufonamide preparation.
– Colour – loss is proportional to decrease in the concentration.
– Oxidation of vitamin A in an oily solution
– Photochemical degradation of chlorpromazine in aqueous solution
– Intravenous infusion.
– Drug released from transdermal drug delivery systems

• Mechanism
– In zero order reaction, the rate must depend on some factor
other than the concentration term.
– The rate limiting factors are solubility as in suspensions or
absorption of light as in certain photochemical reactions 10
• Derivation
– The rate equation for zero order can be derived as follows
– Consider a reaction which the molar concentration [A] of
reactant A is decreasing. We write the rate as:
-dA/dt = k0
– Let, A0 = concentration @ t=0; initial concentration &
– At = concentration at a given t time.
– Then

At t

 dA  k  dt
A0
0
0

At  A0   k 0t or At  A0  k0t

A0  At
11/06/20 k0  11
t
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• Linear relationship between the concentration and
time in zero-order reactions
• If the initial concentration is ‘a’ and the
concentration at any time is ‘c’ then above equation
is changed to
(a  c)
k0  or c  a  k0t
t

• Calculation of half-life (t½):

• c = a/2 t = (t½)
– Substitute this in previous equation,
( 1 )a
we get
( a  c ) a  ( a / 2) 2 a
t1    
2 k0 k0 k0 2k 0
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• Calculation of shelf-life
– Shelf – life is represented as t90 with units of time.
• c = 90 a/100 t = t90
– substituting these in previous equation, we get

t90 
 a  0.9a 

0.1a
k0 k0

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• Example:
– A multi sulpha preparation is exposed to 40C & the
intensity of colour was measured.
– The initial absorbance of the solution at 500 nm was
0.56 .
– After 90 days, the absorbance was decreased to 0.34
– Estimate the reaction rate assuming that the colour
fading follows zero order.

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• Solution
– Reaction rate is mathematically expressed in terms of the
rate constant.
– Data:
• A0 = 0.56, At= 0.34 t =90 days; k0 = ?

• Recall
A0  At
k0 
= 0.56-0.34/90 = t2.44*10-3 day–1
• k0 = 0.56-0.34/90 = 2.44*10 day
• Or 0.00244 day–1

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 Apparent Zero–Order – Suspensions
• The concentration in solution depends on the
drug's solubility
– As the drug decomposes in solution, more drug is released
from the suspended particles so that the concentration
remains constant
• The amount of drug in solution remains constant
despite its decomposition with time
• The reservoir of solid drug in suspension is
responsible for this constant approach

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• The equation for an ordinary solution, with no reservoir of drug, is
first order
-d[A]/dt = k1[A]
– [A] = concentration of undecomposed drug@time ‘t’
– k1 = first-order rate constant
• When [A] is maintained constant due to the reservoir of solids in case
of suspension, k1[A]= k0
• the rate equation (above) changes to;
-d[A]/dt =k0
– The equation represents zero order.
– It is referred as apparent zero-order equation, being zero order
only because of suspended reservoir, ensures constant
concentration.
– Once all the suspended particles have been converted to solution,
the system changes to first order reaction
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• Solid state decomposition (Tablets, Dry Syrups & Dry
Solids)
– In solid state, when the drug is exposed to high humidity,
the moisture settles (participates) on the solid surface
– A part of the drug on the surface goes into solution &
develops a saturated aqueous drug layer around the solid
particle.
– Thus system behaves like a suspension, & follows a zero –
order.
– Once the entire solid is exhausted, the system exhibits first
order rate.
– When decomposition occurs in small amounts, it is difficult
to distinguish between zero and first order reactions
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 First Order Reactions
– The rate of a reaction is proportional to the first power
of the concentration of a reactant.
– Defined as a reaction in which the rate of reaction
depends on the change of concentration of one
reactant.
– Consider the reaction
AProduct
• -dc/dt  c - dc/dt = kc
– ‘c’ is concentration
– ‘k1 is the specific rate constant for first order
Integrating between conc. C0 at time t=0 and
concentration C at some later time t
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Fall in concentration of a decomposing drug with time

C0
Concentration

½C0

C1 -dc/dt
Concentration at t ∞

C∞
t1/2
Time
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 • To test if the reaction is a first order, plot the natural
logarithm of a reactant concentration versus time and see
whether the graph is linear.
• If it is linear, and has a negative slope, it must be a first order
reaction
• The first-order rate constant, k1, has the units of time–1.
• The half-life and shelf-life for first-order reactions are given
by:

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• The half-life and the shelf-life are constants
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 the
remaining 50% of the drug to decompose to
50%.
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• Example
– Hydrogen peroxide decomposition was followed
by measuring the volume of oxygen liberated. The
initial concentration of Hydrogen peroxide was
57.9 cm3. After 65 minutes, the drug
concentration in the product was found to be 9.6
cm3.
– Assuming that the drug degradation is first-order,
what should be the k and what is the remaining
concentration after 25 min?

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 Solution:

• K= 2.303/65 log (57.9/9.6)

• = 0.0277/min or 0.0277 min–1

• 0.0277= 2.303/25 * log (57.9/c)

c = 29.01

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• Example
– Calculate the time half-life and shelf-life (t90, at
which it has decomposed to 90% of its original
concentration, i.e., 10% decomposition) at 25oC
for an aspirin solution. k = 4.5 x 10-6 sec-1.

– t1/2 = 0.693/(4.5 x 10-6 sec-1) = 154,000 sec = 42.8

hr

– t90 = 0.105/(4.5 x 10-6 sec-1) = 23,333 sec = 6.5 hr

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 Pseudo First Order Reactions
• A reaction which is originally a second order, but it is
made to behave like a first order reaction.
• The rate depends on the concentration terms of two
reactants
• Therefore the rate equation would be
– dc/dt = k2 [A] [B]
• Where A & B are reactants in the reaction & k2 is the
second order rate constant
• The reaction conditions are maintained in such a manner
that one reactant (say B) is present in large excess
compared to the concentration of the other substance (A).
• Therefore, the concentration of ‘B’ does not change
significantly during the course of the reaction.
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 • - dc/dt = k2 [A] [constant] = k1 [A]
– Thus, the rate depends on the concentration of one
reactant (on A), i.e., first order reaction.
– This type of reaction is also termed as apparent first
order.
• Eg;
1. Hydrolysis of ester (methyl acetate or ethyl acetate)
catalyzed by H+ ions. Here, the concentration of H+ ions
remains constant. Therefore, the rate solely depends on
the concentration of the ester.
2. Hydrolysis (inversion) of sucrose to glucose & fructose in
aqueous solution catalyzed by acid (water is in large
excess)
3. Acid catalyzed hydrolysis of digoxin
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 Second Order Reactions
• A+ B  Products

• When the speed of the reaction depends on the

concentrations of A and B with each term raised to the
first power, the rate of decomposition of A is equal to
the rate of decomposition of B, and both are
proportional to the product of the concentration of
the reactants.
d[A] d[B]
     k 2 [A][B]
dt dt
Examples of second order reactions
– Hydrolysis of ester by an alkali (saponification).
• CH3COOC2H5 + NaOH → CH3COONa + C2H5OH
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• If a and b are the initial concentrations of A and B,
respectively, and x is the concentration of each
species reacting in time t, the rate may be written as
dx
 k 2 (a - x)(b - x)
dt
– where
• k2 is the second-order rate constant
• dx/dt is the rate of reaction, and a-x and b-x are the concentration
of A and B respectively, remaining at time t.
• When both A and B are present in the same
concentration so that a=b,
dx
 k 2 (a - x) 2
dt
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• On integration using the
conditions that x = 0 at x t
t = 0 and x = x at t = t dx
• when x/a(a-x) is plotted
0 (a  x) 2  k 2 0 dt
against t, a straight line
 1   1 
results if the reaction is     k2 t
second order a  x a 0
x
 k2t
a(a  x)
1  x 
k2   
at  a  x 

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Linear plot of kinetic data for a second-order reaction

slope = k2
x/a(a-x)

Time

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• In the general case, A and B are not present in equal
concentration,
dx
 k 2 (a - x)(b - x)
dt

• On integration and resolving

2.303 b(a  x)
log  k2t
a-b a(b  x)

2.303 b( a  x )
k2  log
t(a - b) a (b  x)
• A plot of log[b(a-x)/a(b-x)] against t should yield a
straight line with a slope of (a-b) k2 / 2.303
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 Linear plot of kinetic data for a second-order reaction

slope = (a-b)k2/2.303
log[b(a-x)/a(b-x)]

Time

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• Example
• The saponification of ethyl acetate at 25ºC is shown
below:
– CH3COOC2H5 + NaOH  CH3COONa + C2H5OH
• The initial concentrations of both reactants in the
mixture were 0.01M.
• The change in concentration of alkali (x) during 20
minutes was 0.00566 mole/liter, therefore (a-x) =
0.00434 mole/liter
• Compute (a) rate constant (b) half life(t1/2)

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• Solution
k2=(1/at)[x/(a-x]
k2 =[1/0.01(20)][(0.00566)/(0.00434)]
=6.52 liter/mole-min

The half life of a second-order reaction is:

t1/2=1/ak

=1/0.01(6.52)=15.3 minutes

Note: only when the initial concentration of the

reactants are identical

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 Aulton, M.E., Pharmaceutics: The Science of Dosage
Form Design. Churchill Livingstone, Edinburgh.

 Martin Patrick J Sinko, Martin’s Physical Pharmacy

and Pharmaceutical Sciences. 5th Ed, Lippincott
Williams & Wilkins, USA.

 G.S.Banker and C.T.Rhodes (ed). Modern

Pharmaceutics, 4th Ed, Marcel Dekker, Inc. New York.