kinetics and drug stability

05/03/2023 vignan pharmacy college 1

KINETICS AND DRUG STABILITY


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


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)


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 dtdC

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 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 .


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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