The document discusses drug stability and degradation kinetics. It defines drug stability as the ability of a pharmaceutical dosage form to maintain its physical, chemical, therapeutic and microbial properties during storage and usage. The main criteria for acceptable stability are that each active ingredient retains its chemical integrity and potency. Degradation kinetics aims to predict a drug's intrinsic stability by determining the order of degradation reactions and their rate constants. Common degradation pathways include hydrolysis, oxidation, photolysis and racemization. The Q10 method can be used to estimate shelf life based on a drug's activation energy.

1. Presented By: Anvita Jadhav
M. Pharm (IP)
1

2. DRUG STABILITY
 Drug stability means the ability of the pharmaceutical
dosage form to maintain the physical, chemical,
therapeutic and microbial properties during the time of
storage and usage by the patient.
2

3. CRITERIA FOR ACCEPTABLE LEVELS OF
STABILITY
Type of Stability Conditions maintained throughout the shelf life of
the drug product
Chemical Each active ingredient retains its chemical integrity and
labeled potency within the specified limits.
Physical The original physical properties, including appearance,
palatability, uniformity, dissolution, & suspendability are
retained.
Microbiologic Sterility or resistance to microbial growth is retained
according to the specified requirements. Antimicrobial
agents retain effectiveness within specified limits.
Therapeutic The therapeutic effect remains unchanged.
Toxicologic No significant increase in toxicity occurs. 3

4. IMPORTANCE OF DEGRADATION KINETICS
 Development of optimum formulation (preformulation studies)
 Determine the optimum storage conditions (temperature, light,
humidity)
 Selecting the proper container for dispensing (glass or plastic,
clear or opaque, cap liners)
 Predicting the shelf life of the drug
 Anticipating drug excipient interactions.
 Stabilization of the drugs against degradation
4

5.  Degradative reactions in pharmaceutical
formulations take place at definite rates & are
chemical in nature.
 Degradation kinetics aims to predict the intrinsic
stability of a drug in order to anticipate problems
that may arise during development
5

6. RATE & ORDER OF REACTION
 According to the law of mass action:
 The rate of a chemical reaction is proportional to the product of molar
concentrations of the reactants each raised to a power equal to the
number of molecules of the substance undergoing reaction.
 aA + bB + ….. Product
 The velocity at which a reactant or a product undergoes chemical
change is called the rate of a reaction. The rate, velocity or speed of a
reaction is given by the expression
where dc is increase or decrease of concentration over a time interval
dt.
6
,

7. ORDER OF REACTION
 The order of reaction is defined as the manner in
which the rate of a reaction varies with the
concentration of reactants. The overall order is the
sum of the exponents of concentration terms that
afford a linear plot.
 For above reaction, order of reaction = a + b
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8.  Zero order reaction
 First order reaction
 Second order reaction
 Pseudo order reaction
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Pseudo zero order reaction
Pseudo first order reaction
ORDER OF REACTION

9. ZERO ORDER REACTION
 The rate of the reaction doesn't depend on concentration of the reagent(s).
 The rate expression for chemical reaction,
A B
 Rate of reaction = - d[C]/dt = k
where, [C] indicates decreasing concentration of reagent & k indicates rate
constant.
 Integrating of rate equation between initial concentration Ao at t = 0 & At,
concentration after t = t we obtain,
9

10.  The initial concentration corresponding to Co is ordinarily
written as ‘a’ & concentration remaining at time ‘t’ as ‘x’. When
this linear equation is plotted with x on vertical axis against t on
horizontal axis, the slope of the line is equal to – k.
10
Concentration
Time
Slope = – k

11. FIRST ORDER REACTION
 Rate of the reaction depends on concentration of
any one reagent.
 The rate expression for chemical reaction,
A B
 Rate of reaction =
 Integrating above rate equation between initial
concentration Co at t = 0 & Ct, concentration after
t=t, we obtain,
11

12.  The initial concentration corresponding to Co is ordinarily
written as ‘a’ & concentration remaining at time ‘t’ as ‘x’.
When this linear equation is plotted with ‘log Ct’ on vertical
axis against ‘t’ on horizontal axis, the slope of the line is
equal to
12
Time
Slope = – kt/2.303
logCt

13. SECOND ORDER REACTION
 The rate of the reaction depends upon concentration of two
reactants.
 There are two cases,
 Case 1: when the initial concentrations of A & B are identical or
two molecules of the same reactant are involved in the reaction.
A + B products or
2A products
 Where, a = initial concentration of the reactant or reactants and
x = concentration of the reactant changed in time t.
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14. Integrating rate equation between initial concentration ‘a’ at t = 0 &
(a-x), concentration after t = t, we obtain,
 Case 2: When the initial concentrations of the two reactants are
different, i.e.,
A + B products
 Assume the initial concentration of two reactants to be a & b
 Integrating above equation,
 (a - x) and (b - x) are the concentrations of A and B after time
interval, t.
14

15. PSEUDO ORDER REACTION
 Originally of higher order but made to behave like lower order
reaction
1. Pseudo zero order reaction:
In the solid state, many drugs decompose according to
pseudo zero order rates as reactions.
It frequently occur in drugs formulated as pharmaceutical
suspensions.
2. Pseudo first order reaction:
It can be defined as a second order reaction that is made to
behave like a first order reaction.
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16. DEGRADATION PATHWAYS
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Hydrolysis
Oxidation-Reduction
Photolysis
Racemization

17. HYDROLYSIS
 Many pharmaceuticals contain ester or amide functional
groups, which may undergo hydrolysis in solution.
 Examples of drugs that tend to undergo hydrolytic cleavage of
an ester or amide linkage are anesthetics, antibiotics,
vitamins, & barbiturates.
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18. 1. ESTER HYDROLYSIS
 The hydrolysis of an ester into a mixture of an acid & alcohol
essentially involves the rupture of a covalent linkage between a
carbon atom & an oxygen atom.
 The alkaline hydrolysis of an ester is irreversible where as acid
hydrolysis of an ester is reversible.
 The general form of the kinetic equations to express acid or
base-catalyzed hydrolysis is as follows:
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19.  This is done by keeping the OH- or H- at a considerably higher
concentration than the ester concentration or by keeping
constant through the use of buffers. This would cause the
previous equation reduce to:
 Whenever possible, first order kinetics expression have been
employed in the study of the degradation of drugs by ester
hydrolysis, but at times, second order kinetics expression have
been employed.
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20. 2. AMIDE HYDROLYSIS
 Amides are relatively stable than esters.
 Pharmaceuticals such as niacinamide, phenethicillin,
barbiturates, & chloramphenicol degrade by amide hydrolysis.
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21. 3. RING ALTERATION
 A hydrolytic reaction can proceed as a result of ring cleavage
with subsequent attack by hydrogen or hydroxyl ion.
 Its examples are hydrochlorothiazide, pilocarpine & reserpine.
Quite often equilibrium kinetics is associated with such
mechanisms.
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22. OXIDATION–REDUCTION
 The oxidative decomposition of pharmaceutical compounds is
responsible for the instability of preparations such as steroids,
vitamins, antibiotics, & epinephrine
 These reactions are mediated either by free radicals or by
molecular oxygen.
 Autoxidation is most common form of oxidative decomposition
of pharmaceuticals, which involves a free radical chain process.
A:B A*+ B*
 These radicals are highly unsaturated & readily take electrons
from other substances, causing oxidation. 22

23. FUNCTIONAL GROUP SUSCEPTIBLE TO OXIDATION
Functional Group Drugs/Excipients
Aldehydes Paraldehyde
Amines Clozapine
Carboxylic acids Fatty acids
Conjugated dienes Vitamin A
Ethers Diethyl ether
Nitrites Amyl nitrite
Phenols Catecholamine, Morphine
Thioethers Cholpromazine
Thiols dimercaprol
23

24. PHOTOLYSIS
 Photolytic degradation (as it applies to pharmaceutical stability)
is the degradation that results from exposure to ultraviolet or
visible light in the wavelength range of approximately 300–800
nm.
 Photo degradation rates are therefore directly dependent on the
amount of incident radiation and on the amount of radiation that
is absorbed by the compound or the formulation.
 It is important to remember that a compound may undergo
photolytic degradation even if it does not itself absorb radiation
in the UVA or visible region.
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25. o If the molecules absorbing the radiation take part themselves in the
main reaction, the reaction is said to be photochemical.
o Where the absorbing molecules do not themselves participate directly
in the reaction, but pass on their energy to other molecules that do,
the absorbing substance is said to be a photosensitizer.
o The photodegradation of chlorpromazine through a semiquinone free-
radical intermediate follows zero order kinetics.
o Alcoholic solutions of hydrocortisone, prednisolone, &
methylprednisolone degrade by reactions following first-order kinetics.
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26. RACEMIZATION
 An optically active substance loses its optical activity without
changing its chemical composition
 In general, undergo degradation in accordance with first order
kinetic principles
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27. SHELF LIFE
 It can be defined as the period of time during which a
pharmaceutical product, if stored correctly, is expected to comply
with the specification as determined by stability studies on a number
of batches of the product.
 The shelf life is used to establish the expiry date of a batch. The
shelf-life is the time required for 10% of the material to disappear; it
is the time at which concentration has decreased to 90% of its
original concentration.
Zero order
First order 27

28. Q10 METHOD OF SHELF LIFE ESTIMATION
 Q∆T is a factor used to estimate the change in the
reaction rate constant with changes in temperature,
∆T. Ea is activation energy established for a
reaction.
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Ea
kcal/mole
Q5
25o-30o C
Q10
25o-35o C
Q15
25o-40o C
10 1.32 1.73 2.24
15 1.52 2.27 3.36
20 1.75 2.99 5.04
25 2.01 3.93 7.55
Change in reaction rate constants due to the temperature effects

29.  The Q10 approach, based on Ea, which is
independent of reaction order, is described as
 In usable terms, Q10, the ratio of two different
reaction rate constants, is defined thus
The equation for Q10 shelf life estimates is
Where, is the estimated shelf life, is the given shelf life
at a given temperature, and ∆T is the difference in the
temperatures T1 and T2. 29

30. ARRHENIUS EQUATION
 Arrhenius observed that most reaction rates depend on
the following three factors
A. Fraction of molecules possessing energy of activation
(Ea) or greater
B. number of collisions per second
C. fraction of molecules having the correct orientation
 Arrhenius noted that the increase in reaction rate is not
linear with increase in temperature in most reactions.
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31.  Svante August Arrhenius (1859–1927) developed a
mathematical relationship between k (the rate
constant) and Ea (energy of activation).
 Therefore, if k is determined experimentally at
several temperatures, and ln k vs 1/T is plotted Ea
can be calculated from the slope of the plot.
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Slope = – Ea/R
Ink 1/T

32. 32
Where, k2 & k1 are rate constants at
temperature T2 & T1 respectively.
The results of Arrhenius analysis
can be useful in predicting the
impact of changes in storage
conditions or climatic zone on
expiration dating interval of a given
drug-product.
In practice, multiple levels of
thermal stress are applied to the
formulation so that appropriate
shelf-life estimates can be made for
normally expected marketing
conditions.
Slope = – Ea/R
Ink
1/T

33. ICH RECOMMENDED EVALUATION
 The shelf life of a commercial drug product must be
determined in the commercial container closure at the
defined storage conditions.
 ICH requires at least 12 months stability data at the time
of NDA submission.
 Most products require at least 24 months to be
commercially viable.
 The ICH Q1E recommended how the 12 months data
may be used to predict long-term stability. 33

34. CONCLUSION
 Degradative reactions (hydrolysis, oxidation-
reduction, photolysis, racemization) in
pharmaceutical formulations take place at definite
rates & are chemical in nature.
 Degradation kinetics is important aspect in
preformulation studies, determination of the
optimum storage conditions, prediction of shelf life,
stabilization of the drugs against degradation.
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35. REFERENCE:
 Lachman/Lieberman’s The Theory and Practice of Industrial Pharmacy,
Editors: Roop Khar, SP Vyas, Farhan Ahmad, Gaurav Jain, Chapter 28
Kinetic Principles and Stability Testing, Pg. No. 1036-1072, 2014.
 Steven W. Baertschi and Patrick J. Jansen, Chapter 2 Stress Testing: A
Predictive Tool, Pharmaceutical Stress Testing (Predicting Drug
Degradation), Taylor & Francis Group, LLC, 2005.
 Steven W. Baertschi and Karen M. Alsante, Chapter 3 Stress Testing: The
Chemistry of Drug Degradation, Pharmaceutical Stress Testing (Predicting
Drug Degradation), Taylor & Francis Group, LLC, 2005.
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