Kinetics and drug
stability
By
Mrs. Harshita M. Pharm. (Ph.D.), [Link]
Department of Pharmaceutics
College of Pharmacy, University of Hafr Al-Batin, KSA
LEARNING OBJECTIVES
After completion of this chapter, the students
should be able to know:
Introduction
Rates and order of reaction
Method for determining the order of reaction
Complex reaction
Factor affecting rate of reaction
Kinetics of drugs decompositions
Definition
Kinetics & Drug stability
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
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
Consider of process.
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)
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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
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
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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 dtequation..........2
Integration of equation-2 gives:
C - C o = - 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
dC = −K C
d
t
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.
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
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.
Acid catalyzed 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
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
Suggested
Readings
Thank
you
