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Kinetics and S Tability

This document discusses kinetics and drug stability. It defines kinetics as the study of the rate of processes, whether chemical or physical. Kinetic studies are useful for understanding reaction mechanisms and predicting changes over time. The order of a reaction depends on the number of concentration terms that determine the rate. First-order reactions depend on one concentration term, pseudo-first order reactions incorporate a constant concentration term into the rate constant, and second-order reactions depend on two concentration terms. Zero-order reactions have a constant rate independent of concentrations. The half-life is the time for a concentration to reduce by half. Temperature affects reaction rates according to the Arrhenius equation. Accelerated stability testing exposes products to stressful conditions to rapidly

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Solomon
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33 views

Kinetics and S Tability

This document discusses kinetics and drug stability. It defines kinetics as the study of the rate of processes, whether chemical or physical. Kinetic studies are useful for understanding reaction mechanisms and predicting changes over time. The order of a reaction depends on the number of concentration terms that determine the rate. First-order reactions depend on one concentration term, pseudo-first order reactions incorporate a constant concentration term into the rate constant, and second-order reactions depend on two concentration terms. Zero-order reactions have a constant rate independent of concentrations. The half-life is the time for a concentration to reduce by half. Temperature affects reaction rates according to the Arrhenius equation. Accelerated stability testing exposes products to stressful conditions to rapidly

Uploaded by

Solomon
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PPTX, PDF, TXT or read online on Scribd
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Chapter Five: Kinetics and drug stability

Solomon G.A , B.Pharm , MSc

1
Introduction
• Kinetics is the study of the rate at which
processes occur.
• The changes may be chemical
(decomposition of a drug, radiochemical
decay) or physical

2
Kinetic studies are useful in
1. gives an insight into the mechanisms of
the changes involved, and
2. Allows a prediction of the degree of
change that will occur after a given time
has elapsed.

3
Order

• This is the number of concentration terms


that determine the rate.
• The law of mass action states that the rate
depends on the product of concentrations
of the reactants

4
first order

• The rate of reaction = k\ [N2O5], i.e. there is only one


concentration term
• Many drug decompositions on storage and the passage
of drugs from one body compartment to another, e.g.
lumen of the intestine into blood, follow first-order
kinetics.
The rate of reaction is most simply defined as the
concentration change divided by the corresponding
time change:
5
first order

The negative sign is used because concentration falls as


time increases.
.For real changes these small changes are summed
(integrated), usually from the start of the process (time =
0, concentration = C0) to the concentration, c, remaining
at any other time, t.
6
first order

7
first order
• Thus a plot of In c against t is a straight
line with intercept c0 and gradient -k.
Example 7.1
Consider the following. A tritiated cardiac stimulant is administered by i.v. injection.
Blood samples have the following radioactivity counts per second (cps):

8
first order

9
Pseudo first order
• Consider the hydrolysis of ethyl acetate:

• Strictly the reaction is second order and


the rate of reaction is expressed as:

10
Pseudo first order
• However, in a dilute aqueous solution of
ethyl acetate, [H2O] is very large
compared to [CH3COOEt] and hardly
alters during the course of the reaction.
• [H2O] can be taken as a constant and
incorporated into the second-order rate
constant, k':

11
Pseudo first order

where k'= k[H2O].

Thus the reaction is, in effect, first order with a


rate constant k'. This applies to many drug
decompositions by hydrolysis in aqueous
solution.
12
Second order
• Rate depends on the product of two
concentration terms

relies on the collision of two HI molecules.

13
Second order

14
Second order

15
Zero order
• the rate of reaction is independent of the
concentration of the reactants, i.e. the rate
is constant.
• apply to processes occurring at phase
boundaries, where the concentration at the
surface remains constant either because
reaction sites are saturated (enzyme
kinetics, drug receptor interaction)
• or are constantly replenished by diffusion of
fresh material from within the bulk of one
phase
16
Zero order
• Thus, a plot of c against t is a straight line
with gradient k. Units of k from Eqn 7.5 are
cone time -1,

17
Zero order

18
Half-life (fi)
• This is the time taken for the concentration
(of, say, a drug in solution) to reduce by a
half. Rearrangement of the integrated
equations for t (Eqns 7.2, 7.4 and 7.6)
gives:

19
20
Determination of order and rate
This can achieved in two ways:
1. Substituting the data into the integrated
equations and observing which plot is a
straight line;
2. Finding t1\2 values at different stages of
the reaction and noting whether and how
they vary with 'starting' concentration

21
22
Effect of temperature on reaction rate

• Generally, increasing temperature


increases the rate of reaction, and an
often-quoted rough guide is that a 10°C
rise doubles the rate constant
Arrhenius theory
• This can be developed from simple basic
ideas and leads to an equation that is
formally identical with the transition state
theory
23
Arrhenius theory

• The original proposition was that if two


molecules collided they would react.
• The collision number, Z, can be calculated
from the kinetic theory of gases, and it was
found that the number of molecules
reacting per second, µ, was much smaller
than Z..

24
Arrhenius theory
• The theory was modified to propose that
the colliding molecules must have
sufficient energy to form an unstable
intermediate, which breaks down to form
the product
• The fraction of molecules with at least this
activation energy, E, was calculated by
Boltzmann as

so that µ= .
25
• The rate constant k is proportional to µ.
So, writing k as a µ gives:

µ is thousands of times smaller than

Thus an orientation factor, P, often with a very small value, must


also be included:

The rate constant k is proportional to µ. So, writing k as a µ gives:


26
• Over a small temperature range the
change in Z with T is negligible compared
to

• that in the term, so that aPZ is a


constant, A
• A is called the 'frequency factor', as it is
related to the frequency of correctly
aligned collisions.
27
This is the Arrhenius equation, and may
also be written as:

28
• so that a plot of In k (or log k} against (1/T)
is a straight line, enabling the calculation
of E and A from the gradient and intercept
(remember that T must be in K, not °C).

29
ACCELERATED STABILITY TESTING

• To assess the stability of a formulated


product it is usual to expose it to 'high
stress', i.e. conditions of temperature,
humidity and light intensity that are known
from experience to be likely causes of
breakdown

30
ACCELERATED STABILITY TESTING

• High stress conditions enhance the


deterioration of the product and therefore
reduce the time required for testing.
• This enables more data to be gathered in
a shorter time, which in turn will allow
unsatisfactory formulations to be
eliminated early in a study and will also
reduce the time for a successful product to
reach the market.
31
The objectives of such accelerated tests
may be
1. The rapid detection of deterioration
2. The prediction of shelf-life
3. The provision of a rapid means of quality
control

32
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34
Q10 Method of Shelf Life Estimation

• The Q10 method of shelf life estimation


lets the pharmacist estimate shelf life for a
product that has been stored or is going to
be stored under a different set of
conditions

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