The document discusses drug stability, emphasizing its ability to maintain properties during storage and usage. It highlights the importance of degradation kinetics in predicting drug stability, determining optimum storage conditions, and establishing shelf life based on various chemical reaction orders. Additional content covers types of reactions affecting drug stability, such as hydrolysis, oxidation-reduction, and photolysis, along with methodologies for evaluating shelf life and stability testing.

1. Degradation kinetics
Ravish Yadav

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.
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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.
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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
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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
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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.
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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. Order of Reaction
• Zero order reaction
• First order reaction
• Second order reaction
• Pseudo order reaction
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Pseudo zero order reaction
Pseudo first order 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,
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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.
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Concentration
Time
Slope = – k

11. Determination of t1/2
Let c = co /2 and t1/2 = t
substitute in equation;
c = co – k t
t1/2 = co / 2K
Note: Rate constant (k) and t1/2 depend on co
Determination of t0.9
Let c = 0.9 co and t= t0.9
substitute in equation;
c = co –k t
t90% = t0.9 = 0.1 co / k
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12. 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,
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13. • 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
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Time
Slope = – kt/2.303
logCt

14. Determination of t1/2
Let t = t1/2 and c = co /2
substitute in ln c = ln co – Kt
t1/2 = ln 2/ K = 0.693 / K
K units = 0.693 / t1/2 = time-1
Determination of t0.9
Let t = t0.9 c = 0.9 co
substitute in ln c = ln co – Kt
t0.9 = 0.105 / K and K = 0.105/ t0.9
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15. 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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16. 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.
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17. 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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18. Degradation pathways
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Hydrolysis
Oxidation-Reduction
Photolysis
Racemization

19. 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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20. 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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21. • 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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22. 2. Amide hydrolysis
• Amides are relatively stable than esters.
• Pharmaceuticals such as niacinamide, phenethicillin, barbiturates, &
chloramphenicol degrade by amide hydrolysis.
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23. 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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24. 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.
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25. 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 25

26. 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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27. o If the molecules absorbing the radiation take part themselves in the main
reaction, the reaction is said to be photochemical.
oWhere 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.
oThe photodegradation of chlorpromazine through a semiquinone free- radical
intermediate follows zero order kinetics.
oAlcoholic solutions of hydrocortisone, prednisolone, & methylprednisolone
degrade by reactions following first-order kinetics.
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28. 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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29. 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
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30. 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

31. • 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.
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32. 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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33. • 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

34. 34
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

35. 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.
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36. 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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37. 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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