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PRESENTATION
ON
DEGRADATION KINECTICS AND MECHANISM
BY,
NAME : K.SAILAKSHMI,
ROLL NO : 256213886016,
,
DEPARTMENT: M.PHARMACY(PHARMACEUTICS).
UNDER THE GUIDENCE,
OF
Mrs.YASMIN BEGUM
M.pharmacy.

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CONTENTS
Definitions
Degradation kinetics pathways
Drug degradation mechanisms

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Definitions:-
 Kinetics:
DEGRADATION KINETICS
pharmacokinetics is the mathematical analysis of process of ADME
 Rate of reaction:
The rate of a reaction can be expressed either decrease or
Increase in concentration per unit time
dx/dt
 Order of reaction:
order of reaction express expermentally determined dependence
of rate upon reactant concentration.
dc/dt = - kc n
Where,K = rate constant, n = order of reaction(0,1,2)
 Half life:
It is defined as the time taken for 50% of the reaction to occur.
This time is called the half life of the reaction.(t 1/2).

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DEGRADATION KINETICS PATHWAYS
The degradation of kinetics mathematically divided as follows:
 Zero order reactions
 First order reactions
 Second order reactions
 Third order reactions

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 ZERO ORDER REACTION
A zero-order reaction has a rate that is independent of the concentration of the
reactant(s).
dc/dt = -ko
Where,
ko = zero order rate constant (mg/ml)
dc = -k0dt
By integrating,
c-co = -kot
Where,
co = conc. Of drug at t=0
c = conc. Of drug at to under go reaction at time t.

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 Half life of zero – order reaction:
When t = t ½ , c = c0/2
There fore,
co/2 = co – ko t1/2
t ½ = co/2k0
Thus,
t1/2 of zero order is constant by proportional to initial conc.
Of drug co & inversely to zero order rate constant ko.

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 EXAMPLE:
Decomposition of NH3 in presence of molybdenum or tungsten is
a zero-order reaction. [Mo]
2NH3 → N2 + 3H2
The surface of the catalyst is almost completely covered by
NH3 molecules. The adsorption of gas on the surface cannot change by
the pressure or concentration of NH3. Thus, the concentration of gas
phase remains constant although the product is formed.Therefore, this
reaction zero order kinetics.

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 FIRST ORDER REACTION
A reaction is said to be first order if its rate is determined by the change of one
concentration term only.
dc/dt = - kdt
By integrating,
ln c =ln co-kt
c = coe-kt
Since ln = 2.303log
Log c =log c0 – kt/2.303
k = 2.303/t log c/c0

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 Half life of first order reaction:
If c = c0/2 at t1/2
t1/2 = 0.693/k
Examples of first order reactions
1. Decomposition of H2O2 in aqueous solution
H2O2 → H2O + 1/2 O2
2.Hydrolysis of methyl acetate in presence of mineral acids.
Acid
CH3COOCH3 + H2O → CH3COOH + CH3OH

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PSEUDO FIRST ORDER REACTION
This occurs when the rate of process is proportional to the concentration of
only one reactant even though the reaction involves several reactant species
EXAMPLE:
Procaine hydrochloride undergo hydrolysis obeys pseudo first order reaction.

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SECOND ORDER REACTION:
A reaction is said to be of second order if its reaction rate is determined by
the variation of two concentration terms.
The kinetics of second order reactions are given as follows:
(i) When concentration of both reactants are equal or two molecules of the
same reactant are involved in the change, i.e.,
A + B → products
or 2A → products
dx/dt = k(a(a-x)3
On solving this equation,
k = 1/t.x/a(a-x)
where a = initial concentration of the reactant or reactants and
x = concentration of the reactant changed in time t.

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(ii) When the initial concentrations of the two reactants are different,
i.e.,
A + B → products
Initial conc. a b
dx/dt = k(a-x)(b-x)
k = 2.303/t(a-b) log10 b(a-x)/a(b-x)
(a-x) and (b-x) are the concentrations of A and B after time interval, t.
Half life of second order reaction:
t1/2 = 1/ka
Examples of second order reactions
Hydrolysis of ester by an alkali (saponification).
CH3COOC2H5 + NaOH → CH3COONa + C2H5OH

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THIRD ORDER REACTIONS
A reaction is said to be of third order if its rate is determined by the variation
of three concentration terms.
When the concentration of all the three
reactants is same or three molecules of the same reactant are involved, the
rate expression is given as
3A → products
A + B + C → products
dx/dt = k(a-x)3
On solving this equation,
k = 1/t.x(2a-x)/(2a2 (a-x)2)
Examples of third order reacting
1. Reacting between nitric oxide and oxygen
2NO + O2 → 2NO2
2. Reaction between nitric oxide and chlorine.
2NO + Cl2 → 2NOCl

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 DRUG DEGRADATION MECHANISMS
TYPES OF DRUG DEGRADATION
 CHEMICAL DEGRADATION
○ HYDROLYSIS  ESTER  AMIDES  BARBITURATES, HYDANOINS
& IMIDES  SCHIFF BASE AND OTHER REACTION INVOLVING
CARBON NITROGEN BOND CLEAVAGE
○ DEHYDRATION
○ ISOMERIZATION & RACEMIZATION
○ DECARBOXYLATION & ELIMINATION
○ OXIDATION
○ PHOTODEGRADATION

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R1
O
X + H2O R1
O
OH
+ HX
Carboxylic acid derivatives

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ESTER HYDROLYSIS
• Ester hydrolysis is a chemical degradative process during which
the ester group reacts with water and yields an acid and an alcohol.
• It occurs because of the disruption of covalent linkage between carbon
and oxygen atom
Examples:
drugs like aspirin, cocaine, procaine

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AMIDES HYDROLYSIS
Amide bonds are commonly found in drug molecules.
•Amide bonds are less susceptible to hydrolysis than ester bonds
because the carbonyl carbon of the amide bond is less electrophilic
(the carbon-to-nitrogen bond has considerable double bond
character)
• The leaving group, an amine, is a poorer leaving
EXAMPLES
.
• Acetaminophen, chloramphenicol,lincomycin, indomethacin and
sulfacetamide, all of which are known to produce an amine and an acid
through hydrolysis of their amide bonds.
.

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• β-Lactam antibiotics such as penicillins and cephalosporins, which
are cyclic amides or lactams, undergo rapid ring opening due to
hydrolysis

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BARBITURATES, HYDANTOINS & IMIDES
• Barbiturates, hydantoins, and imides contain functional groups related to amides
but tend to be more reactive.
• Barbituric acids such as barbital, phenobarbital and amobarbital, undergo ring-opening
hydrolysis.
• Decomposition products formed from these drug substances are susceptible to
further decomposition reactions such as decarboxylation.

24. SCHIFF BASE AND OTHER REACTION INVOLVING
CARBON NITROGEN BOND CLEAVAGE
• Benzodiazepines such as diazepam,oxazepam, and nitrazepam undergo ring
opening due to reversible hydrolysis of the amide and azomethine bonds
• Benzodiazepinoxazoles(oxazole-condensed benzodiazepines) such as
oxazolam,flutazolam, haloxazolam, and cloxazolam are not Schiff bases but
undergo ring opening due to hydrolysis.
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DEHYDRATION
○ Sugars such as glucose and lactose are known to undergo
dehydration to form 5- (hydroxymethyl)furural.
○ Erythromycin is susceptible to acidcatalyzed dehydration.
○ prostaglandins E1 and E2 undergo dehydration followed by
isomerization.
○ Batanopride undergoes an intramolecular ring- closure reaction in the
acidic pH range due to dehydration whereas streptovitacin A exhibits
two successive acid-catalyzed dehydration reactions,.
Lactose/glucose 5-(hydroxymethyl furfural)
MILLARD REACTION

26. ISOMERIZATION
○ Isomerisation is the process by which one molecule is transformed into
another molecule which has exactly the same atoms, but the atoms are
rearranged e.g. A-B-C → B-A-C
○ Pilocarpine undergoes epimerization by base catalysis.
○ Tetracyclines such as rolitetracycline and ergotamine exhibit epimerization
by acid catalysis.
○ Etoposide converts reversibly to picroetoposide, a cis- lactone, and then
hydrolyzes to cis-hydroxy acid in the alkaline pH region.
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RACEMIZATION
• Racemization refers to partial conversion of one enantiomer into
another.
• Epinephrine is oxidized and undergoes racemization under strongly
acidic conditions.

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DECARBOXYLATION
• Drug substances having a carboxylic acid group are sometimes
susceptible to decarboxylation,
• 4-Aminosalicylic acid is a good example.
• Foscarnet also undergoes decarboxylation under strongly acidic
conditions.

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ELIMINATION
• In elimination reaction reaction some groups of the substance
is eliminated.
• Trimelamol eliminates its hydroxymethyl groups and forms
formaldehyde.
• Levothyroxine eliminates iodine.

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OXIDATION
• Oxidation mechanisms for drug substances
depend on the chemical structure of the drug and
the presence of reactive oxygen species or other
oxidants.
• Catechols such as methyldopa and epinephrine
are readily oxidized to quinones.
N
R2
H
R1
O O R1
HO N
R2
R1
N
R2
O O R1
N+ O-
R2
Amines

31. PHOTODEGRADATION
• Photodegradation is the process by which light- sensitive drugs or excipient
molecules are chemically degraded by light, room light or sunlight.
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 The variation of degradation depends on the wavelength of light, shorter
wavelengths because more damage than longer wavelengths.
 Before a photodegradation reaction can occur, the energy from light
radiation must be absorbed by the molecules.
 Photodegradation of the chloroquine and primaquine gives the various
product through different pathways.

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 Two way in which photodegradation can occur are:
The light energy absorbed must be sufficient to achieve the activation energy
Or
The light energy absorbed by molecules is passed on to other molecules which
allow degradation to take place

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REACTION OF AMINES WITH
REDUCING SUGARS
• Reducing sugars readily react with primary
amines, including those of amino acids, through
the Maillard reaction.
• Drug substances with primary or secondary
amine groups undergo this
addition/rearrangement reaction, also called
the .browning. reaction because of the resulting
discoloration.
Examples are the reaction of amphetamine,isoniazid dextroamphetamine
sulfate and norphenylephrine with sugars such as lactose and the degradation
products of sugars, such as 5-(hydroxymethyl)furfural.
• Sulpyrine forms ann addition product with glucose

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CONCLUSION
•Kinetics allows chemists to predict how the speed of a reaction will
change under different reaction conditions.
•The study of kinetics is important because it can elucidate information
about the mechanism of a reaction and can also allow chemists to be
more efficient in the laboratory.
•It also help full to improve the product stability.

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REFERENCES
• The theory and practical of industrial pharmacy-Lachmann and libermann.
• Text book of pharmaceutics-Bentley’s.
• www.google.com

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