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

Degradation kinetics

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Page 1: Degradation kinetics

Presented By: Anvita Jadhav

M. Pharm (IP)

1

Page 2: Degradation kinetics

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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Page 3: Degradation kinetics

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

Page 4: Degradation kinetics

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 degradation4

Page 5: Degradation kinetics

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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Page 6: Degradation kinetics

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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,

Page 7: Degradation kinetics

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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Page 8: Degradation kinetics

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

Page 9: Degradation kinetics

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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Page 10: Degradation kinetics

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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Co

ncen

trati

on

Time

Slope = – k

Page 11: Degradation kinetics

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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Page 12: Degradation kinetics

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

log

Ct

Page 13: Degradation kinetics

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.13

Page 14: Degradation kinetics

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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Page 15: Degradation kinetics

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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Page 16: Degradation kinetics

DEGRADATION PATHWAYS

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Hydrolysis

Oxidation-Reduction

Photolysis

Racemization

Page 17: Degradation kinetics

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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Page 18: Degradation kinetics

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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Page 19: Degradation kinetics

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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Page 20: Degradation kinetics

2. AMIDE HYDROLYSIS

Amides are relatively stable than esters.

Pharmaceuticals such as niacinamide, phenethicillin,

barbiturates, & chloramphenicol degrade by amide hydrolysis.

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Page 21: Degradation kinetics

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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Page 22: Degradation kinetics

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

Page 23: Degradation kinetics

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

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Page 24: Degradation kinetics

PHOTOLYSIS

Photolytic degradation (as it applies to pharmaceutical stability)is the degradation that results from exposure to ultraviolet orvisible light in the wavelength range of approximately 300–800nm.

Photo degradation rates are therefore directly dependent on theamount of incident radiation and on the amount of radiation thatis absorbed by the compound or the formulation.

It is important to remember that a compound may undergophotolytic degradation even if it does not itself absorb radiationin the UVA or visible region.

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Page 25: Degradation kinetics

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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Page 26: Degradation kinetics

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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Page 27: Degradation kinetics

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

Page 28: Degradation kinetics

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

Page 29: Degradation kinetics

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

Page 30: Degradation kinetics

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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Page 31: Degradation kinetics

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

In k

1/T

Page 32: Degradation kinetics

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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

In k

1/T

Page 33: Degradation kinetics

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

Page 34: Degradation kinetics

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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Page 35: Degradation kinetics

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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