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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: 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).

DEGRADATION KINETICS

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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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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.

EXAMPLE:

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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 andx = concentration of the reactant changed in time t.

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(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

(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)

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 + H2OR1

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.

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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

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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

NOH

R2

R1O ON

R2

R1

N+

O-

R2

R1O O

Amines

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PHOTODEGRADATION

• Photodegradation is the process by which light- sensitive drugs or excipient molecules are chemically degraded by light, room light or sunlight.

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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