Kinetics of stability and stability testing

KINETICS OF STABILITY
STABILITY TESTING
SUBMITTED BY-
ANKIT KUMAR MALIK
SUBMITTED TO-
DR.YASMIN SULTANA
DEPARTMENT : Pharmaceutics
School Of Pharmaceutical Education and Research
JAMIA HAMDARD

INTRODUCTION
Chemical kinetics provide the basis to predict drug
stability.
The extent of inactivation of drug due to various
environmental adverse conditions can be understood
from the drug stability studies.
It is expressed as a rate process.
These studies help to predict the expiry period (shelf
life) of a product.

RATE AND ORDER
The rate, velocity or speed of a reaction is
given by ± (dc/dt). Here dc is the small
change in the concentration within a
given time interval dt.
Order of a reaction is defined as the
number of concentration terms on which
the rate of a reaction depends when
determined experimentally.

.
• 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.
Consider the following reaction:-
DRUG A DRUG B

.
• 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)

Zero order reaction is defined as a reaction in
which the rate does not depend on the
concentration terms of the reactants.
This is mathematically expressed as:
dC/dt = -ko
Where ko is the specific rate constant for a zero
order
Zero order process is also called as “Constant
rate process”
ZERO ORDER REACTION

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/dt = -KC
Where,
K = first –order rate constant( per hour)
C = concentration of the reactant

GRAPH OF FIRST-ORDER KINETICS SHOWING LINEAR RELATIONSHIP
BETWEEN RATE OF REACTION AND CONCENTRATION OF DRUG

SECOND ORDER REACTION
• Second order reaction is defined as a reaction in which the rate depends on the
concentration terms of two reactants each raised to the power one.
• Consider the following reaction:-
• The rate equation can be written as :-
• Where [A] and [B] are the concentration of A and B, respectively, and k2 is the specific
rate constant for second order. In other words, the rate of reaction is first order
with respect to A, and again first order with respect to B. So the overall order of this
reaction is second order.

Graph of Second order kinetics

PSEUDO FIRST ORDER REACTION
• Pseudo first order reaction is defined as a reaction which is originally a
second order, but is made to behave like a first order reaction.
• In second order reaction, the rate depends on the concentration terms of
two reactants. Therefore the rate equation would be:-

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)
 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

.
REVERSIBLE REACTIONS
• The simplest reversible reaction is one in which both the forward and the
reverse steps are first-order processes:
PARALLEL OR SIDE REACTIONS
• Parallel reactions are common in drug systems, particularly when organic
compounds are involved.

.
SERIES OR CONSECUTIVE REACTIONS:
• Consecutive reactions are common in radioactive series in which a parent
isotope decays by a firstorder process into a daughter isotope and so on
through a chain of disintegrations.
• We take a simplified version of the degradation scheme of glucose as
illustrative of consecutive-type reactions.
• The depletion of glucose in acid solution can be represented by the
following scheme , 10 where 5-HMF is 5- hydroxymethylfurfural:
• where A is glucose, B is 5-HMF, and C is the final breakdown products.

FACTORS AFFECTING RATE OF REACTION
 TEMPERATURE
 LIGHT
 SOLVENT
 IONIC STRENGTH
 DIELECTRIC CONSTANT
 CATALYSIS
 SURFACTANT
 DRUG STABILITY
 DISSOLUTION
 DRUG RELEASE

METHODS OF DETERMINATION OF
REACTION ORDER
• There is no straight forward method to theoretically know the
order of a reaction.
• The exact order can be determined experimentally. The
following methods are employed to decide the order of a
reaction.
1. GRAPHIC METHOD
2. SUBSTITUTION METHOD
3. HALF LIFE METHOD

GRAPHIC METHOD
• This pictorial method may be more reliable because
deviations from the best fit line can be easily observed.
Conduct the kinetic experiment and collect the data on
the time course of changes in the concentration of the
reactants. Plot the data on a graph paper as per the
general principles of each order.
• Decide which graph gives a better fit for a straight line.
The reaction is considered to be of that order.

SUBSTITUTION METHOD
• Conduct a kinetic experiment and collect the data on
the time course of changes in the concentration of
reactants. Substitute the data in the integral equation of
zero, first, and second order reactions to get k values.

.
• Select the order in which k values at different time
periods remain constant within the experimental
errors. The reaction is considered to be of that order.

HALF LIFE METHOD
• Calculate the average k value using the data for zero, first, and
second orders as given in substitution method or graphic
method. Then, estimate the t1/2 values for each time period in
the kinetic study.
• Equations are as follows:-

STABILITY TESTING
The purpose of stability testing is to provide evidence on how
the quality of an active pharmaceutical ingredient or
medicinal product varies with time under the influence of a
variety of environmental factors such as temperature,
humidity, and light, and to establish a re-test period for the
active pharmaceutical ingredient or a shelf life for the
medicinal product and recommended storage conditions.

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

STRESS TESTING
•Stress testing of the active pharmaceutical ingredient can help identify
the likely degradation products, which can in turn help establish the
degradation pathways and the intrinsic stability of the molecule.
• Stress testing is likely to be carried out on single batch of the active
pharmaceutical ingredient. It should include the effect of temperature
(in
10C increment) above that for accelerating testing , humidity (e.g., 75%
RH or greater) where appropriate oxidation and photolysis on the API.
• The testing should evaluate the susceptibility of the API to hydrolysis
across a wide range of pH values when in solution or suspension.
•Photo stability testing should be an integral part of stress testing

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 .
• If the slope of this line is determined from the results of accelerated tests
at high temperatures.
• Substitution of this value of k into the appropriate order of reaction allows
the amount of decomposition after a given time to be calculated.
• This approach involves, and preliminary experiments are therefore
necessary to determine this order.

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

STORAGE CONDITIONS
• API should be evaluated under storage conditions (with
appropriate tolerance) that test its thermal stability and, if
applicable, its sensitivity to moisture.
• If long term studies are conducted at 25ºC ± 2ºC/60% RH ±
5% RH and “significant change” occurs at any time during 6
month testing at the accelerated storage condition, additional
testing at the intermediate storage condition should be
conducted and evaluated against significant change criteria.

TYPES OF STABILITY STUDIES
 Long term stability studies
Accelerated stability studies
Testing frequency
Packaging container

TESTING FREQUENCY
•For long term studies, frequency of testing should be sufficient to
establish the stability profile of the pharmaceutical product.
•For products with a proposed shelf life of at least 12 months, the
frequency of testing at the long term storage condition should
normally be every 3 months over the first year, every 6 months over
the second year, and annually thereafter through the proposed shelf
life.

PARAMETERS CHECKED DURING
TESTING
•Dissolution/ release of pharmaceutical product
•Assay /percentage purity of pharmaceutical product
• Physical characters of pharmaceutical product
•pH (in case of liquid)

STORAGE OF PHARMACEUTICAL
PRODUCTS
• Appropriate storage of raw materials which includes
drugs, excipients and finished products is necessary.
• Storage of medicinal products maintains the physical,
chemical and biological properties.
• Major areas which demand careful consideration of
storage are hospitals, marketplace of retailers and
wholesalers.
• All medicinal products should be stored in such a way as
to avoid contamination.

METHODS FOR STORAGE OF
PHARMACEUTICAL PRODUCTS
Some of the methods are discussed in the following
sections.
1. Storing of products in well-closed containers
2. Storing the products by protection from light
3. Storing the products in a cool place
4. Storing the products by the addition of other
substances

Kinetics of stability and stability testing

Kinetics of stability and stability testing

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