KINETICS AND STABILITY STUDIES OF DRUGS

BY
PROF. S.I. OFOEFULE

Introduction
Chemical Kinetics is the study of rate of chemical changes taking place during chemical reaction.
As applied to pharmaceutical formulations, it includes a study of:

(a) A study of physical and chemical changes in drugs and dosage forms.
(b) Factors influencing the rate of these chemical reaction.
(c) Accelerated stability testing and prediction of shelf life.

The extent of inactivation or degradation of drugs due to various environmental adverse

conditions can be understood from the drug stability studies. Chemical kinetics are employed in
the determination of:

(a) Stability of drug (t½) i.e. time taken for the concentration of the drug to reduce to half under
stated sets of conditions (i.e. temperature, humidity, pH, etc.).
(b) Shelf life (t0.9) – this will be defined later.
(c) Expriration date – this will be defined later.

Rate and order of Reaction

 The rate or speed or velocity of chemical reaction is given by dc/dt where dc is the initial
small change in the concentration of a drug within a given time, dt.
 Order of a reaction is defined as the number of concentration terms on which the rate of
reaction depends on when determined experimentally.
 There are various order of reaction such as zero order, first order second other, pseudo -first
order. Most pharmaceutical products degrade by either First order or Zerio order.
Discussion here will centre on Zero order and First order degradation kinetics.
(a) Zero Order: Zero order reaction is defined as a reaction in which the rate does not depend
on the concentration terms of the reactants. This is mathemaqtically expressed as:
−dc
= K0
dt

Where K0 is the specific rate constant for a zero order.

In Zero order, when the concentration of the drug degraded is ploted against time, graph (A)
results, while when the amount remaining is plotted against time, graph B results.

(A)
Conc. Amount The slope of the
Mg/L remaining line of gives K0

Time Time
 −dc
Note that = K0, can be written as
dt

-dc = Kodt. This equation is in the form of equation of a straight line, i.e. Y = MX
Where a plot of Y against X gives M as slope. Similarly a graph of –dc verses dt, will give a
straight line with K0 as slope as represented in B above.
b) First Order: First order reaction is defined as a reaction in which the rate of reaction
depends on the concentration of the reactants, mathematically, the first order rate equation is
written as
−dc
&C
dt

−dc
= K1C
dt

C is concentration of the reactant, and IC1 is the specific rate constant for first order.

Methods of Determining Order of Reaction

There are basically three methods of determining order of reaction:
1. Graphical Method.
2. Substitution Method.
3. Half Life Method.

Graphical Method: This involves subjecting the drug product to at least four elevated
temperatures such as 40, 50, 60 and 700C and at 75% Relative humidity. Temperature regulated
ovens are usually used to store quantities of the drug product at the different temperature. This
can be pictured as follows:

400C 500C 600C 700C

ooooooo Tablets ooooooo ooooooo Tablets ooooooo
ooooooo ooooooo ooooooo ooooooo

Oven A Oven B Oven C Oven D

Tablets are sampled from each of the oven at different time intervals and analysed for the quantity of drug
remaining. For instance from the oven A, the tablets are analysed at 4 days interval, oven B at 3 days interval, ovan
C at 2 days interval and oven D on daily basis. At least four sampling and analysis should be done for each oven.
The amount of drug remaining at each sampling time is plotted against the time from where the degradation rate
constant K is estimated from the slopes of the graphs as shown.
 Amount
of drug 40
remaining
50

60

70

Time

Substitution Method
For Zero order:
Ao−At
K0 = A0 = Initial concentration
t
At = Conc at time t
t = time
First order:
2.303 Co
K1 = log K0 = Co = Initial concentration
t Ct
Ct = Concentration at time t
t = time
a kinetic experiment, as in graphical method is conducted and data collected is substituted in the
integral equation of zero, first order, etc. to get K. The order in which the k values at different
time period remain constant with the limits of experimental error is considered to be the order of
reaction.