Drug stability and chemical Kinetics UNIT V

1
Prof.( Dr)Rakesh
Kumar Sharma 3/20/2024
UNIT V BP403T

Objective of the drug stability
Studies
 Todetermine theshelf life.
 Toprovide better safety to the patients.
 Toprovide optimum storage condition.
 Toselect the primary package.(Container-
closure)
 Togather information during preformulation
stage to produce a stable product.
3/20/2024
Prof.( Dr)Rakesh

Introduction to Chemical kinetics
• 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.
3/20/2024
Prof.( Dr)Rakesh

Rate and order (Zero, 1st, 2nd, Pseudo 1st)
• 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.
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Prof.( Dr)Rakesh

Zero Order Reaction
• 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:
• Where k0 is the specific rate constant
for a zeroorder
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Prof.( Dr)Rakesh

Zero Order Reaction
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Prof.( Dr)Rakesh

First Order Reaction
• First order reaction is defined as a
reaction in which the rate of reaction
depends on the concentration of one
reactant.
• Mathematically, the first order rate
equation can be written as:
• Where c is the concentration of the
reactant and k1 is the specific rate
constant for first order 3/20/2024
Prof.( Dr)Rakesh

First Order Reaction
3/20/2024
Prof.( Dr)Rakesh

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.
3/20/2024
Prof.( Dr)Rakesh

Second Order Reaction
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Prof.( Dr)Rakesh

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
•
3/20/2024
Prof.( Dr)Rakesh

Methods of determination or 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
3/20/2024
Prof.( Dr)Rakesh

1.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.
3/20/2024
Prof.( Dr)Rakesh

1.Graphic Method
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Prof.( Dr)Rakesh

• 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.
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Prof.( Dr)Rakesh

• 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.
3/20/2024
Prof.( Dr)Rakesh

3. 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.
3/20/2024
Prof.( Dr)Rakesh

Why Stability studies are Important?
The stability studies are important for the following reasons
Assurance to the patient: This is the assurance given by the
manufacturers that the patient would receive a uniform
dose throughout the shelf life.
Legal requirement: The drug control administrations insist
on manufacturers on conducting the stability studies to
prove the identity, strength, purity and quality of the drug in
the conditions of normal storage.
Rakesh Kumar Sharma 3/20/2024
Prof.( Dr)Rakesh

The USP prescribes the following criteria for acceptable levels of
stability
.
Type of stability
Prof.( Dr)Rakesh 3/20/2024
Conditions to be maintained during the shelf life of the
product.
Chemical Retains its labelled chemical potency
Physical Appearance, uniformity, dissolution etc are to be retained
Microbiological Retain sterility, effectiveness of preservatives etc.
Therapeutic Drug action remain unchanged
Toxicologic No significant increase in toxicity

Physical degradation of
Pharmaceutical products
Loss of volatile constituents: Medicinal agents such as iodine,
camphor, menthol, ethyl alcohol, chloroform have the tendency to
evaporate from the product during the storage.
Nitroglycerine tablets may loose its potency due to volatilization of
medicament. The preventive measure includes keeping the product
in well closed containers and store in cool place.

Loss of water: loss of water from the product leads to decrease in
weight, rise in concentration of the drug and increased potency.
Products such as emulsions exhibit cracking. The preventive
measure includes keeping the product in well closed containers
and store in cool place.
Absorption of water: absorption of water from the atmosphere
increases the weight of the product, dilute the dose and decrease
the potency. Gelatin capsules will absorbs moisture and become
soft and sticky. The preventive measure includes keeping the
product in well closed containers.

Color change: color change indicates some kind of chemical
decomposition of active ingredients. Aspirin tablets become
pick and ascorbic acid tablets turns yellowish brown.
Adrenaline on exposure to air becomes red. Protect the
product from light and air.
Crystal growth: fluctuations in the temperature of storage
cause crystal growth. When the temperature is lowered the
solution becomes supersaturated, precipitation crystal growth
of drug is observed.

Chemical Decomposition of Drugs
All medicinal agents are to be investigated for their
decomposition before being marketed. A few
important decomposition reactions are enumerated
here.
Hydrolysis: Drugs with ester or amide functional
groups react with one molecule of water and
undergoes hydrolysis. Reaction between ionic drugs
proceeds faster than with neutral molecules.
Further hydrolysis reactions are catalysed by H+ and
OH- ions. Hydroxyl ions catalyzed hydrolysis by 100
to 1000 times more actively than hydrogen ions.
Drugs that contain ester group include Aspirin,

Protection against hydrolysis: Hydrolysis reactions are known to occur in
presence of moisture, catalytical species H+ and OH- ions.
Buffers: Drugs may be stabilized by use of buffers. Type of buffer and
optimum pH should be established. For example: pilocarpine is highly
active in alkaline pH, because it occurs as unionized form. But at alkaline
pH, it is highly irritating to the eye and also precipitates from the
solution.
Therefore to prevent hydrolysis acidic pH has to be selected. Boric acid
buffer of a pH 5.0 with low buffer capacity is selected. A stronger buffer
is not used since upon instillation into the eye; the pH of the solution is
able to rise to that of tear secretions (pH7.4) with consequently
formation of the more active basic form of the drug.

Complexation: Hydrolysis of Benzocaine in aqueous solution can be
inhibited by the addition of caffeine. As a result of complexation the
attack of catalytic species on benzocaine may be reduced. The rate
of hydrolysis now will depends on the amount of uncomplexed free
benzocaine present in the solution. Other drugs which may be
stabilized by complexation are procaine, tetracaine etc.

Suppression of solubility: when the solubility of a drug decreases
the concentration of drug in solution phase will be decreased.
Hence the rate of hydrolysis is reduced.
Additives: citrates, dextrose, sorbitol and gluconate, when
combined with the drugs, the solubility of drugs will be
suppressed, probably because of decreased hydration of drug
molecules.

Salts: The degradation of penicillin can be prevented by using
poorly soluble procaine penicillin in the dosage form.
Derivatives: poorly water soluble derivatives such as esters of
drugs can be used to reduced the tendency of hydrolysis.
Example: erythromycin propionate, erythromycin stearate,
chloramphenicol palmitate.

Choice of solvent: Non-aqueous solvents e.g alcohol and propylene
glycol, have often been used to replace a portion, or all, of the
water in a solution in order to reduce hydrolysis of a drug. For
example an elixir of phenobarbitone sodium contains considerable
quantities of glycerin and alcohol.
Removal of water: Store the drug in dry form. When desire
reconstitute the product. Example: streptomycin dry powder for
injection. Other examples include ampicillin, amoxicillin dry
powders for injection.

Oxidation: The general principals that govern an oxidation
reaction may be as follows.
Presence of atmospheric oxygen.
Free radical mediated oxidation. Light provides the necessary
energy to initiate the oxidation process.
The presence of trace metals accelerates the rate of oxidation.
Organic peroxides promote the chain reactions in oxidation
process.
Oxidation reactions are catalysed by H+ and OH- ions.

Factors affecting the rate of oxidation
Dilution: Dilution of an oxidizable compound with an inert
solvent will decrease the rate of oxidation. For example in oily
vitamin solutions the vitamin is present in very low
concentration.
Temperature: The rate of oxidation of an organic compound is
increased with increase in the temperature of storage. For
example: the rate at which hydroperoxides break down in to
aldehydes, ketones and fatty acids is accelerated at temperature
in excess of 50oc.

The presences of pro-oxidants: The pro-oxidants accelerate the
rate of autoxidation.
The hydroperoxides formed during the auto oxidation are themselves
pro-oxidants. The heavy metals for example copper and iron, also
have a pro-oxidant effect.
The degree of unsaturation of the organic compound: Highly
unsaturated compounds are more susceptible to autoxidation and
therefore oxidize at rates greater than compounds having a lower
degree of unsaturation. For example linoleic acid is much more
rapidly oxidized on exposure to air than oleic acid.

Protection against oxidation
Antioxidants:
Ideal antioxidant has the following properties
effective in low concentrations
soluble in the proposed vehicle
Non-toxic, non irritant, odorless and tasteless. Stable
and effective over wide range of pH .
Should not react chemically with other constituents
present.

Tocopherols are the naturally occurring
antioxidants. Other examples are butylated
hydroxyl anisole, butylated hydroxyl toluene,
propyl gallate, ascorbyl palmitate.
These are fat soluble antioxidants, acts by
inhibiting the free radical chain reactions.

Water soluble antioxidants acts by preferentially
undergoing oxidation instead of the drug itself.
Examples are sodium metabisulphite, sodium
formaldehyde sulphoxylate, thioglycolic acid,
cysteine etc.

Chelating agent: addition of chelating agent to a product will
be useful when traces of heavy metals catalyse the
oxidation.
Compounds such as EDTA, citric acid tartaric acid form
complexes with heavy metals.
Example addition of EDTA to the buffer system prevents the
degradation of drugs such as dexamethasone sodium
phosphate and ascorbic acid.

Micellar solubilisation:
surfactants such as polysorbate 80 prevent the oxidation of
ascorbic acid above critical micelle concentration.
Buffers: buffers impart stability when the oxidation is
catalysed by H+ and OH- ions. Choose a buffer with
appropriate pH to maintain maximum stability of the
product.

Environmental Control Measures
Prevent the exposure to light: Morphine sulphate injection USP
and ascorbic acid injection is protected from light by using amber
color ampoules.
Oxygen free environment: oxygen enhances oxidative
degradation. Therefore, replace the air in the container (injection
vials, ampoules) with inert gases such as nitrogen or carbon
dioxide.
Low temperature storage: since high temperature enhances the
rate of reaction, store the product in a cool place.

Decarboxylation: These reactions are mainly
observed when a parenteral solution contains sodium
carbonate. During autoclaving, the carboxylic groups
will be knocked off. To prevent this
pass carbon dioxide gas into the solution for one
minute. Seal the container prior to autoclave.

Absorption of carbon dioxide: Solutions absorb carbon
dioxide from the atmosphere. Sodium hexabarbitone
solution basic pH absorbs CO2 converts to acidic pH
hexababitone precipitate.
Solutions of potassium hydroxide, sodium hydroxide, calcium
hydroxide and lead subacetate become turbid due to
formation of insoluble carbonates. They are therefore stored
in well-filled, well closed containers.

Volatile nasal decongestants, amphetamine and propylhexedrine
also absorbs carbon dioxide from the atmosphere. The solution of
hexobarbitone can absorb carbon dioxide and this result in
precipitation of hexobarbitone. This is a serious problem in the
preparation of intravenous solutions of soluble barbiturates. They are
therefore distributed as sterile powders in vials with instructions to
dissolve immediately before use in water for injection free from
carbon dioxide.

Recemization: it is the inter conversion of dextro rotatry and
leavo rotatry form of drugs. The conversion of (-) adrenaline
greater biological activity to (±) adrenaline 50% reduction in
biological activity.
Epimerization: In this case the compound has more than one
asymmetric carbon atoms. While one symmetric atom remains
static the other carbon rotates to give epimer.
Ergometrine solution converts to less active epimer
ergometrinine.
To prevent epimerization and racemisation, protect the
product from light and heat. Maintain optimum pH.

Influence of Temperature on drug
decomposition
The speed of many reactions increases about two to
three times with every 10o rise in temperature.
Arrhenius equation explains the effect of
temperature on rate of a reaction.
k = A e- Ea/RT
Where: k: specific rate constant
A: frequency factor or Arrhenius factor
Ea: energy of activation
R: Ideal gas factor (1.987 cal/mol,deg)
T: absolute temperature.

Energy of activation is defined as the minimum energy that a
molecule should possess so that molecular collisions produce the
product.
Arrhenius factor is defined as frequency of collisions which can
occur between molecule.
A is the product of molecular collisions and probability factor of
collisions which give a product.
Take logarithms both sides log k = log A – Ea/2.303RT

Estimation of k: conduct the reaction at several
temperatures. Determine the concentration of the reactant
at different time periods at each temperature. Draw the
graphs as per the principles of the different orders for each
temperature. From the slopes of the lines, calculate the k
value for each temperature.

Estimation of energy of activation:
Draw the graph by taking log k on y-axis and 1/T on x-axis.the
intercept will be log A and slope is equal to Ea/2.303R.
To get a line we need the log k values at least at three
temperatures.

Accelerated stability studies for
determination of Shelf Life
The objective of accelerated stability
studies is to predict the shelf life of a
product by accelerating the rate of
decomposition, preferably by increasing
the temperature.
Method: Drug preparations are stored at
elevated temperatures ranging from 400c
to 900c. During different time intervals
samples are withdrawn and the drug
content is estimated using assay method.

Draw a plot by taking concentration undecomposed against
time at different temperatures (from 400c to 900c). Estimate
the value of k for each temperature

log k values are then plotted reciprocal of absolute
temperature. A linear relationship is desirable. Energy of
activation can be calculated.

Extrapolate the straight line to room temperature
(250c) and read the log k25 value on Y-axis.
Substitute the k25 value in the equation of an
appropriate order to get shelf life of the product at
room temperature.

Limitations:
Accerlerated stability studies are valid only when the breakdown
depends on temperature.
Stability predictions at elevated temperatures are of little use when
the degradation is due to microbial contamination, photochemical
reaction.
Stability studies are meaningless when the product looses its
physical integrity at high temperature. For example:
• Coagulation of suspending agents
• ( methylcellulose)
• Denaturation of proteins Cracking of emulsion
• Loss of consistency of ointments.

Stability Testing of Pharmaceutical dosage forms
The shelf life of the product depends on its storage
temperature and for susceptible products, also on humidity.
World is divided in to four climate zones, recognized by
international conference on Harmonization (ICH). They are
based on observed temperatures and relative humidity.
Zone I
Temperate Canada, New Zealand,
Northern Europe, Russia,
UK
21oC 60%RH
Zone II Mediterranean and Subtropical Japan, south Europe, USA 26 oC 65%RH
Zone III Tropical(dry) Middle east,
Australia, Argentina
31 oC 60%RH
Zone IV Tropical(wet) Indian subcontinent, china,
brazil, Nigeria, philippines
31oC 70%RH

The testing should cover those features susceptible to change
during
storage and likely to influence quality, safety and/or efficacy.
Stress testing: Carry out in single batch, includes effect of
temperature (100C increments above accelerated testing),
humidity (75%RH or greater) and light.
There must not be any significant change. Where significant
change
occurs test should be conducted under long term conditions.

Storage test conditions: The length of the studies and storage
conditions should be sufficient to cover storage, shipment and
subsequent use.
Following test conditions are suggested.
Study type
Conditions Minimum Time
period
Long term Testing 300c ± 20c/ 65% RH
± 5% 12 months
Accelerated testing 400c ± 20c/ 75% RH
± 5% 6 month

Where significant change occurs during storage under
accelerated testing conditions at 400c ± 20c/ 75% RH ± 5%.The
test should be conducted only under long term conditions.
Significant change is defined as
Loss of 5% or more potency from initial assay value of a batch.
Failure to meet specifications for appearance, physical
properties for example phase separation, caking,
resuspendability, dose delivery per actuation etc.
Failure to meet specification limit for pH
Failure to meet specification limit for dissolution test for
capsules or tablets.

Testing-Sampling frequency
Long term studies: Every 3 months over the first year, every
6 months over the second year, and annually thereafter
through the proposed retest period
Accelerated: a minimum of three time points, including the
initial
and final time points (e.g., 0, 3, and 6 months)

Rakesh Kumar Sharma 12/27/2013 40
Dosage form Test parameters
Tablets Appearance, color, odor, assay, disintegration time, dissolution, hardness, moisture, friability
Hard gelatin capsules Appearance, color, odor, assay, disintegration time, dissolution, moisture and microbiological limit
Soft gelatin capsules Appearance, color, odor, assay, disintegration time, dissolution, moisture, microbiological limit, pH
and leakage
Emulsions Appearance including Phase separation, color odor, assay, pH, viscosity, wt loss, preservative contents,
microbial limit.
Suspensions Appearance, color, assay, pH, redispersibility, viscosity, particle size, wt loss, preservative contents,
microbial limit
Oral powders for reconstitution. Appearance, color, odor, moisture and reconstitution time.
Small volume parenterals Appearance, color, assay, pH, particulate matter sterility, pyrogenicity
Large volume parenterals Appearance, color, assay, pH, particulate matter sterility, pyrogenicity
suppositories Appearance, color, assay, softening range, dissolution, microbial limit.
3/20/2024
Prof.( Dr)Rakesh

12/27/2013
Rakesh Kumar Sharma 41
3/20/2024
Prof.( Dr)Rakesh

Drug stability and chemical Kinetics UNIT V

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