kinetics and drug stability

2/7/2016 vignan pharmacy college 1

CONTENTS
• Introduction
• Rates and order of reaction
• Method for determining the order of reaction
• Complex reaction
• Factor affecting rate of reaction
• kinetics of drugs decompositions
2/7/2016 2vignan pharmacy college

 Drugs stability is defined as the pharmaceutical dosages form
to maintain the physical, chemical, therapeutic and microbial
properties during the time of storage and uses by the patient.
 Stability is defined as the capacity of a drugs substance to
remain within the established specification to maintain its
identity, strength, quality and purity throughout the retest or
expiration during period.
Definition
kinetics & Drug stability

Chemical kinetics is the study of rate of chemical changes
taking place during chemical reaction.
As applied to pharmaceutical formulation , this include a study
of physical and chemical changes in drugs and dosage form,
factor influencing the rate of these chemical reaction, accelerated
stability testing and prediction of shelf life.

RATES AND ORDER OF REACTION
 The velocity with which a reaction or a process occurs is
called as its rate, concentration of drugs influences the rate of
reaction or process is called as the order of reaction or order
of process.
Consider the following chemical reaction
Drug A Drug B

 The rate of forward reaction is expressed as :
-dA/dt
-ve sign = concentration of drugs A decreases with time.
 As the reaction proceeds, the concentration of the drugs B
increases and the rate of reaction can also be expressed as:
dB/dt
 Experimentally, the rate of reaction is determined by
measuring the decrease in concentration of drugs A with
time.

 If c is the concentration of drug A, the rate of decrease in c of
drug A as it is changed to B can be described by expression as
function of time t.
dC/dt = -kc
Where,
k= rate constant
n=order of reaction
If,
n= 0 (zero order process)
n= 1 (first order process)2/7/2016 vignan pharmacy college 7

 The order of a reaction determines the way in which the
concentration of a reactant or reactants influences the rate of a
chemical reaction.
Molecularity of Reaction
 The molecularity of a reaction refers to the numbers of
molecules, atoms, or ions reacting in a elementary process
to give the reactants.
 If only one type of molecules undergoes a change in to
yield the product , the product is said to be unimolecular.

 If two molecules undergoes to change yield the product,
the reaction is said to be bimolecular.
 Reaction that involves more than one steps ( complex
reaction) may have different molecularity and order of
reaction.
 The three commonly encountered rate process:
Zero order reaction
First order reaction
Mixed order reaction

Zero-order kinetics
o Its is also called as constant rate process.
o The reaction is said to be zero-order reaction , if the rate of
reaction is independent of the concentration i.e. the rate of
reaction can not be increased further by increasing the
concentration of reactants.
dc/dt= -KoCo = -Ko equation.....1
Where
Ko = zero-order rate constant (in mg/min)

Rearrangement of equation 1 yields:
dc= -Ko dt equation..........2
Integration of equation 2 gives:
C - Co = - k0 t
where
Co = concentration of drug at t = 0, and
C = concentration of drug yet to undergo
reaction at time t.

Fig. 1. Graphs of zero-order kinetics

First-order kinetics
 Whose rate is directly proportional to the concentration of the
of drugs undergoing reaction i.e. greater the concentration ,
faster the reaction.
First-order process is said to follow linear kinetics
CK
dt
dC

Where
K = first-order rate constant (per hour)

Fig. 2: Graph of first-order kinetics showing linear relationship
between rate of reaction and concentration of drug

Mixed order kinetics
In some instances, the kinetics of a pharmacokinetic
process changes from predominantly first-order to
predominantly zero-order with increasing dose or chronic
medication.
A mixture of both first-order and zero-order kinetics is
observed in such cases and therefore the process is said to
follow mixed-order kinetics.
 Since deviations from an originally linear pharmacokinetic
profile are observed, the rate process of such a drug is called
as nonlinear kinetics. 2/7/2016 vignan pharmacy college 15

Mixed order kinetics is also termed as dose-dependent kinetics as
it is observed at increased or multiple doses of some drugs.
Nonlinearities in pharmacokinetics have been observed in –
 Drug absorption (e.g. vitamin C)
 Drug distribution (e.g. naproxen), and
 Drug elimination (e.g. riboflavin).
The kinetics of such capacity-limited processes can be
described by the Michaelis-Menten kinetics.

Complex reaction
Many chemical reaction encountered in the pharmaceutical
field are not simple reaction of the zero, first, second or third
order but consists of a combination of two or more reaction .
such reaction is known as complex reaction.
Complex reaction may be classified as:
• Reversible reaction
• Parallel reaction
• Consecutive or series reaction

Factor affecting rate of reaction
•Temperature
•Light
•Solvent
•Ionic strength
•Dielectric constant of solvents
•Catalysis
•Surfactants

Kinetics of drugs decomposition
 A drugs in suspension follows apparent zero order kinetics
in which the concentration of the drugs in the solution
remains constant with time.
 When the drugs in the solution degrades or lost by any
means new drugs molecules from the suspended solid
particles dissolved in the solution to keep the concentration
constant at the equilibrium solubility.
That is the solid suspended particles act as reservoir of
drugs.

 Acid catalysed hydrolysis of the digoxin follows pseudo
first order reaction kinetics , here the concentration of H+
remains constant . Therefore the rate slowly depends on the
concentration of digoxin.
 Hydrolysis of chlorbutanol in presence of sodium
hydroxide follows second order reaction.

Strategy of stability testing
 Strategy is important for the stability testing of any dugs to
maintain their shelf life .
To maintain the shelf life of drugs the ICH and WHO
guideline for stability testing should be followed.
 Protection against hydrolysis
 Protection against oxidation

Accelerated stability analysis
Accelerated stability analysis is design to predict stability
and hence shelf life of formulation under normal and
recommended storage condition by carrying out the study
under accelerated condition of temperature, moisture and
light.
Prediction of shelf life
 Shelf life is the time period during which the dosages
form is supposed to retain its original quantity.
 The prediction is based on the arrhenius equation .2/7/2016 vignan pharmacy college 22

Stability of solid dosages form
 The decomposition of drugs in solid dosages form is
more complex than that occurring in the pure drugs.
 The following are the effect of various factor on the
stability in solid dosages form:
Temperature
Moisture
Chemical interaction

Types of stability studies
Long term stability studies
Accelerated stability studies
Testing frequency
Packaging and container

kinetics and drug stability

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