This document discusses various factors that affect the degradation of drugs, including physical degradation, chemical degradation, temperature, solvent, ionic strength, dielectric constant, and catalysis. It provides examples of specific drugs that undergo different types of degradation, such as hydrolysis, oxidation, and photolysis. Equations are presented that describe the effects of temperature, solvent, ionic strength, and dielectric constant on reaction rates. Methods to prevent or minimize different degradation pathways like the use of antioxidants, chelating agents, buffers, and oxygen-free storage are also summarized.

1. GOURAV SINGH 1
Introduction
 Drug degradation is the process of declining the quality of drug to lower
level.
 Physicaldegradation occur due to change in physicalnature of drug.
 Chemical degradation occur due to change in chemical nature of drug.
Physical
Degradation
of
Drug
Physical degradation cause
volatilisation of compound
during storage
The moisture also decrease
the potency of product and
cause degradation.
Change from one state to
another is also sign of
physical degradation.
Change in colour is also due
to physical degradation

2. GOURAV SINGH 2
i) Temperature
High temperature accelerate oxidation, reduction, and hydrolysis reaction
which lead to Drug degradation.
Chemical
Degradation
of
Drug
Due to presence of different
functional group , the drug
undergoes different chemical
reaction
This reaction are sign of chemical
degradation.
This are the following factor that
affect the rate of reaction
Chemical Degradation of Drug
Temperature Solvent Ionic Strength
Dielectric
constant
Catalysis

3. GOURAV SINGH 3
With every 100
C risein temperature, the rate of reaction also rises two or
three times.
The effect of temperature on rate of reaction is explained by Arrhenius
equation, SvanteArrhenius developed a mathematical relationship between K
and Ea
K = Ae-E
a/RT
Where,
K = Specific reaction rate constant
A = Arrhenius factor
Ea = Energy of activation
R = Gas constant (1.987 calories/deg mole).
T = Absolute temperature
The Arrhenius factor (A) is a measureof the frequency of collision between the
reaction molecules. The energy of activation (Ea) is the energy required for
effective collision to causea reaction between the molecules.
Taking natural logarithmon bothside,
In 𝑲 =
−𝑬𝒂
𝑹𝑻
+ In A
By converting this equationtolog base 10, it gives
𝐥𝐨𝐠𝑲 = log A -
𝑬𝒂
𝟐.𝟑𝟎𝟑𝑹𝑻
This representstraightline equation. When graph is plotted by taking log K on y
axis and 1/T on x-axis, a straightline is obtained. The slopeof line will be negative
and equal to Ea/2.303R.
Graph between log K and 1/T
(1/T)→
Log
K

4. GOURAV SINGH 4
When K is determine experimentally at several temperatures, Ea can be
calculated fromslope of the plot of log K vs 1/T.
When measurement are takenfor 2 different temperatures, the Arrhenius
equationcan be writtenas
In K =
−𝑬𝒂
𝑹𝑻
+ In A
By Writing the above equationtwice, one for each of two temperature andthen
substract lower temperature conditionfromthe higher temperature, we get
𝐊𝟐
𝐊𝟏
= 𝐈𝐧 𝐊𝟐 − 𝐈𝐧 𝐊𝟏 = −
𝐄𝐚
𝐑
[
𝟏
𝐓𝟐
−
𝟏
𝐓𝟏
]
Where
K2 is rate of constantat temperature T2
K1 is rate of constantat temperature T1
ii) Solvent
The nature of solvent can also affect the rate of decomposition of drugs. The
relation between reaction rate constantand solubility of reactant and products is
given by
𝐥𝐨𝐠 𝐊 = 𝐥𝐨𝐠 𝐊𝟎 +
𝐕
𝟐. 𝟑𝟎𝟑𝐑𝐓
(∆𝐒𝐚 − ∆𝐒𝐛 − ∆𝐒∗)
Where,
K = Observed reaction rate constant
K0 = Rate constant is infinitely in dilute solution
V = molar volume of solute

5. GOURAV SINGH 5
∆Sa, ∆Sb, and ∆S*
= difference in solubility parameter of solvent and reactant ‘a’,
reactant ‘b’ and activated complex respectively.
From this equationis found that
 If polarity of product> polarity of reactant then reaction rate increases if
the solventis more polar.
 If polarity of product< polarity of reactant then reaction rate increases if
the solventis less polar.
iii) Ionic Strength
The effect of ionic strength on rate of decomposition of drug is explained by the
following equation:
𝐥𝐨𝐠 𝐊 = 𝐥𝐨𝐠 𝐊𝟎 + 𝟏. 𝟎𝟐 𝐙𝐀𝐙𝐁 √𝛍
Where,
K = rate constantof degradation
K0 = rate constantat infinite dilution in which µ=0
µ = Ionic strength of solution
ZA and ZB = the charge on reactant A and B respectively
iv) Dielectric constant
The dielectric constant is used to measure polarity of the solvent.
Dielectric constantshows significanteffect on the rate of reaction.
The effect on the dielectric constant on the rate constant of an ionic reaction,
extrapolated to infinite dilution where the ionic strength effect of zero is
determined by the following equation:

6. GOURAV SINGH 6
𝐈𝐧 𝐊 = 𝐈𝐧 𝐊𝛆= ∞ −
𝐍𝐙𝐀𝐙𝐁𝐞𝟐
𝐑𝐓𝐫∗
𝟏
𝛆
Where,
K(ε= ∞) = Reaction rate constantin a solventof infinite dielectric constant
K = Observed reaction rate in a solvent of dielectric constant(ε)
N = Avogadro’s number
ZA and ZB = Chargeon the two ionic species
e = Unit of electric charge
r*
= Distance between the ionic species in the activated complex
ε = Dielectric constantof the solution.
v) Catalysis
A catalyst is a substancethat either increase or decreasethe rate of reaction but
itself remain unchanged chemically.
The catalyst only makethe reaction faster, it does not affect the yield of the
product.
The catalyst of the reactant form an intermediate complex, which then
decomposeto regenerate the catalyst and the product. Homogenous catalysis
occur when the catalyst and the reactant are in samephase. Acid base catalysis is
most importanttype of homogenous catalysis. Heterogeneous catalysis occur
when the catalyst and the reactant formseparate phasein the mixture.
a. Specific acid-base catalysis
The number of drug decomposed on the addition of acids or bases. When the
rate law of an accelerated decomposition reactions contains a term involving the
concentration of the hydroxylions, the reaction is called specific acid-base
catalysis

7. GOURAV SINGH 7
The magnitude of acid basecatalyzed reaction vary with pH.
For example:-
Hydrogen ion catalysis occur at lower pH range while hydroxylion catalyzes a
higher pH range. The general rate law which express the pH dependence of
specific acid-base-catalyzed reaction, is shown as
𝐝𝐩
𝐝𝐭
= (𝐊𝟎 + 𝐊𝟏[𝐇+] + 𝐊𝟐 [𝐎𝐇−]) [𝐒]
For which the observed rate constantis given by:
𝐊𝐨𝐛𝐬 = 𝐊𝟎 + 𝐊𝟏 [𝐇+] + 𝐊𝟐 [𝐎𝐇−
]
At low pH, the hydrogen ion concentration is high and hence K1 [H+] is greater
than K0 or K2 [OH--
]. Theobserved reaction rate constantbecomes:
𝐊𝐨𝐛𝐬 = 𝐊𝟏[𝐇+
]
And the reaction is specific hydrogen ion catalyzed or acid catalyzed.
Similarly, at higher pH, the hydroxylion concentration is much higher and hence
the term K2[OH--
] aresmall in value, the observed reaction rate is:
𝑲𝒐𝒃𝒔 = 𝑲𝟐 [𝑶𝑯−
]
And the reaction is specified hydroxylions or basecatalyzed. At an intermediate
pH, when the concentrations of hydrogen and hydroxylions arelow or if the
products of K1 [H+
] and K2 [OH--
] aresmall in the value, the observed reaction rate
is:
𝐊𝐨𝐛𝐬 = 𝐊𝟎
In this case, the reaction is said to be solventcatalyzed.
b. General Acid-Base Catalysis

8. GOURAV SINGH 8
Buffer are used to maintain pH of the solution. Buffer salt shows catalytic effects
on drug degradation rate in solution. The reaction is said to be general acid
catalysis if catalytic componentis acidic while reaction is said to be general base
catalysis if catalytic componentis basic.
In general basecatalysis, the proton transfer take place during rate determined
step. Itgenerally function with weak base. While the general acid catalysis
operated with weak acid.
Stability testing
Stability is defined as ability of drug or formulation to remain within fixed
specification of identity and purity upto specific period of time.
The stability of pharmaceutical product also indicate how long a formulation
retain its original form withoutany change
The purposeof stability testing is to provideinformation in how quality of drug
varies with time under the influence of various environmentfactor such as
temperature, pH, light and humidity.
Stability testing is done to determine shelf life of product, to determine of
components used for packaging, and to get information at preformulation stage
so that stable productis obtained at final stage.
Causes of instability and their prevention

9. GOURAV SINGH 9
i) Hydrolysis
If breaking of molecules is due to reaction with water, then it is called hydrolysis.
Itis a step in degradation of substance. Drug such as ester, amides and lactams
undergo hydrolysis.
Drug with ester or amide functional group react with one molecule of water and
undergoes hydrolysis.
Reaction between ionic drugs proceed faster than with neutral molecules.
Further hydrolysis reaction arecatalyzed by H+ and OH- ions. Hydroxylions
catalyses hydrolysis 100 to 1000 times moreactively than hydrogen ions. For
example
a. Hydrolysis of ester:
CH3COOCH2CH2CH3 +H2O CH3COOH +CH3CH2CH2OH
PropylEthanoate water Acetic acid propanol
Causes of Instability and their
Prevention
Hydrolysis Oxidation Photolytic

10. GOURAV SINGH 10
Examples of drug which undergo ester hydrolysis are: procaine, atropine,
aspirin and physiostigmine.
b. Hydrolysis of amide:
Amides hydrolysis to the parent carboxylic acid and the appropriate amine.
Amide are more stable than esters.
O O
R—C—NH—R’ + H2O R – C – OH + R’ –NH2
Amide Carboxylic acid
Example of drug which undergo amide hydrolysis are: Dibucaine,
Ergometrine, Chloramphenicoland barbiturates.
c. Many polyamide polymers such as Nylon 6,6 hydrolyse in presences of
strong acids. This cause depolymerization.
 Protection against hydrolysis:-
Hydrolysis reaction areknown to be occur in presenceof moisture, catalytic
species H+
and OH-
.protectivemeasure should aim at eliminating the influence
of these factor on the drug.
Factors On the drug
Buffer Drug may be stabilized by the useof buffers.
The pH of the solution should be adjusted so that the drug
will have maximum stability and the therapeutics activity.
Complexation Hydrolysis of benzocaine in aqueous solution can be
inhibited by the addition of caffeine which forma
complex.
Other drug which may be stabilized by complexation are:
procaine, tetracaine etc.
Suppression of
solubility
When solubility of a drug decreases, the concentration of
drug in solution phase will be decreased.
Hence, the rate of hydrolysis is reduced.
Now the rate depends on the saturation solubility of the drug and follows zero
order of reaction.
1. Additives Citrates, dextrose, sorbitoland gluconates, when combined
with drugs.

11. GOURAV SINGH 11
Solubility of drug will be suppressed probably, becauseof
decrease hydration of drug molecules.
2 Salts The degradation of penicillin can be prevented by using
poorly soluble salt of procainepenicillin in a dosageform
For examples—benzathine penicillin G
3 Derivatives Poorly water solublederivatives such as ester of drug can be
used to reduce the tendency of hydrolysis.
For examples –erythromycin propionate, erythromycin
stearate.
4 Removal of
water
As the presenceof water is responsiblefor hydrolysis, itis
better to avoid its contact with the drug in the preparation.
This is achieved by-
1. Storing the drug in drug form
2. Using water-immiscible vehicle for the dispersion of
drug
ii) Oxidation
Oxidation involves the removals of electrons froma molecules.
The reaction between the compounds and molecular oxygen is called auto-
oxidation.
In fats and oils, auto-oxidation of unsaturated fatty acid proceeds in presenceof
atmospheric oxygen, light and traces of heavy metal or hydrogen peroxide.
The general principle that govern an oxidation reaction may be listen as follows:
1. The presence of atmospheric oxygen promotes the rate of oxidation.
2. Since oxidation frequently occur free radicals, chain reaction occurs.
3. Presences of trace metals also accelerated the rate of oxidation.
4. Drugs areeither weak acid or bases
5. Oxidation reaction are catalyzed by H+
and OH-
ions.
Drug which decomposeby oxidation pathways aregiven below.

12. GOURAV SINGH 12
Arachis oil Vitamin A
Ethyl oleate Riboflavin
Clove oil Vitamin B12
Cinnamon oils Ascorbic acid
Promethazine Morphine
Epinephrine Prednisolone
The auto-oxidation kinetics of ascorbic acid has been extensively studied. The
overall reaction may be represented as:
𝐶𝐻2𝑂𝐻 CH2OH
O O
+
1
2
𝑂2
𝐶𝑢2+
→
Ascorbic acid Dehydro-Ascorbic acid
Ascorbate ions in solutions
Slow oxidation
Semi quinone
rapid oxidation
Dehydro-Ascorbic acid
OH
H
H
O
OH OH
O
OH
H
O
O
H
Cu2+
O2

13. GOURAV SINGH 13
 Preventive measure
01 Anti-oxidant This agent is to break the free radical chain reaction at
the chain propagation step.
For example:- tocopherols, ascorbic acid etc.
02 Chelating
Agent
These agent are used in heavy metals-Catalysed oxidation
reaction.
Chelating agents (EDTA, citric acid, and tartaric acid)
03 Vehicles For most of the pharmaceutical preparations, water is
used as a solvent or vehicles to dispensethe drug.
04 Surfactant These agent enhances the oxidation rate of ascorbic acid
at low conc.
05 Buffers Buffer solution are helpful in providing maximum stability
to the products.
06 Oxygen free
environments
Oxygen free solventused for manufacturing drug
Eg. Nitrogen and carbon dioxide
07 Low
temperature
Storage
The pharmaceutical products are stored in a cool place
because high temperature enhances the rate of
oxidation.
iii) Photolysis
Photolytic degradation is the degradation of photodegradablemolecules caused
by the
 Absorption of photons.
 Particularly those wavelengths found in sunlight.
 Such as infrared radiation
 Visible light
 Ultraviolet light
Some other example of photochemical reactions are:
1) Ergosterolconverts into vitamin D when exposed to UV light
2) Chlorophyllabsorbs visiblelight and undergoes photosynthesis forming
carbohydrates and oxygen

14. GOURAV SINGH 14
Photo-degradation involves combined action of sunlightand air. Itinvolvethe
process of oxidation and hydrolysis.
Phototoxic drugs arethe examples of Furosemide, acetazolamide, and
cyanobalamin
Photolytic degradation can be prevented by:
1) Packaging of drugs in amber colored bottles
2) Packaging of drugs in cardboards outer
3) Packaging of drugs with aluminium foil overwraps
Accelerated stability testing
In these method, the drug formulation is exposed to elevated temperature for
prolonged period to predict shelf of the formulation.
The stability testing is done to predict the time period upto which the quality of
productremain satisfactory under prescribed storagecondition.
Ich guidelines
ICH stand for “INTERNATIONAL CONFERENCEON HARMONISATION”.
ICH is a jointinitiative involving both regulator and research based industry
representative of the European Union, Japan and USA in scientific and technical
discussion of the testing procedurerequired to access and ensurethe quality and
efficacy of the medicines.
ICH Guidelines are divided into 4 major categories and ICH topics codes are
assigned according to this categories:
Q-Quality
S-Safety

15. GOURAV SINGH 15
E-Efficacy
M-Multidisciplinary
ICH guideline Title
Q1A (R2) Stability Testing of New Drug Substances and products
Q1B Stability Testing photo stability Testing of New Drug
substanceand products
Q1C Stability testing for New DosageForms
Q1D Bracketing and Matrixing Designs
Q1E Evaluation of Stability Data
Q1F Stability Data for Climatic zoneIII& IV
Climatic zones with their temperature and Relative humidity values
Stability studies: storageCondition for productintended to be stored at room
temperature
Stability Study type Storage condition
long term stability studies Duration: 5 years
Temperature: 25 ± 20
C
Relative humidity: 60 ± 5 %
Intermediate stability studies Duration: 6 years
Temperature: 30 ± 20
C
Relative humidity: 65 ± 5 %
Accelerated stability studies Duration: 6 years
Climatic Zone
Zone I
Moderate/Temper
ature climate (210C
/45%RH)
ZoneII
Subtropical and
Mediterrianclimate
(250C60%RH)
Zone III
Hot/Dry climate
(300/35%RH)
ZoneIV
Hot /Humidity
Climate
(300/70%RH)

16. GOURAV SINGH 16
Temperature: 40 ± 20
C
Relative humidity: 75 ± 5 % RH
Predication of shelf life
Arrhenius equation explain the effect of temperature on rate of a reaction.
According to Arrhenius equation, for any 100
rise in temperature, the speed of
reaction increases about 2-3 times.
𝑘 = 𝐴 𝑒−𝐸𝑎/𝑅𝑇
log𝑘 = log𝐴 −
𝐸𝑎
2.303
𝑅𝑇
The step involved in Accelerated Stability Testing in Prediction of shelf life:
1. The preparation is stored at different elevated temperature (40,50,60, and
700
C)
2. Concentration of the reactant at each elevated temperature is also
determined.
3. Samples are withdrawn atdifferent time intervals.
4. The Order of the reaction is determined by plotting the conc. againsttime
and linear relationship is determined.
5. Straight line in a graph permits the estimation of K value from the slope.
6. Similarly the graph are drawn for different elevated temperature. K value
for each temperature are calculated.
7. By using Arrhenius relationship, Log K values are plotted against reciprocal
of absolute temperature, energy of activation can be calculated.
8. The plot is extrapolated to roomtemperature 250
Cto determine K25 value.
9. The K25 value is then substituted into shelf life equation to determine shelf
life of product.

17. GOURAV SINGH 17
700
𝐶
600
𝐶
500
𝐶
Log K 400
𝐶
250
𝐶
(1/T)
DiagramArrhenius plot to predict shelf life of drug
A similar method explained by free and Blythe for liquid products wherethe
decomposition behaves according to the general kinetics laws.
In this case log (% of drug remaining) is plotted against time (in days). Fromthe
graph times for the potency (Concentration) to fall to 90% of the original value
(i.e. t90%) are read at different temperature.
Shelf life of product in days at 250
C
Limitation of Accelerated stability Study
Log t90%
(1/T)
Diagram Plotof t90 against1/T

18. GOURAV SINGH 18
1. This method is not used in caseof complex reaction because of Arrhenius
equation consistof only one rate constanttherefore it is applicable to
simple decomposition mechanism.
2. This method is not applicable if degradation is due to freezing, microbial
contamination, excess agitation etc.
3. This method is valid only if energy of activation lies between 10 to 30
kcal/moles.
4. The products which loose their physicalintegrity at elevated temperature is
not suitable for accelerating testing.
5. This method is not valid when order changes at higher temperature.
DOSAGES FORM EVALUATION PARAMETER
TABLET Appearance, colour, odour, assay, degradation
products, dissolution, moistureand friability.
HARD GELATIN
CAPSULES
Appearance, colour, odour, assay, degradation
products, dissolution, moistureand microbial products.
SOFT GELATIN
CAPSULES
Appearance, colour, odour, assay, degradation
products, dissolution, moisture, microbialproducts, pH
and leakages.
EMULSION Appearance, colour, odour, assay, degradation
products, dissolution, moisture, microbialproducts, pH,
viscosity, preservativecontent, and distribution of
dispersed phaseglobules.
ORAL SOLUTION Appearance, colour, odour, assay, degradation
products, dissolution, moisture, preservativecontent,
microbial limits.
ORAL SUSPENSION Appearance, colour, odour, assay, degradation
products, dissolution, moisture, preservativecontent,
microbial limits, redispersibility, rheological properties.
ORAL POWDER Appearance, colour, moisture, reconstitution time.
Expiration date
Drug expiring date is the date at which the drug’s potency begins to diminish.
The expiry date depends on specified storageconditions.

19. GOURAV SINGH 19
Not all drugs havethe same rate of decomposition, thus expiry dates will differ.
Amoxycillinsuspension has an expiry dates of 14 days when stored at room
temperatures (250
C).
Trimethoprim/ sulphamethoxazole combination tablets havea shelf-life of 5
years when stored below 300
C.