KINETICS OF KINETICS OF DECOMPOSITIONDECOMPOSITION

KINETICS OF DECOMPOSITIONKINETICS OF DECOMPOSITION

INTRODUCTIONINTRODUCTIONDECOMPOSITION PATHWAYSDECOMPOSITION PATHWAYSBASIC KINETIC PRINCIPLESBASIC KINETIC PRINCIPLESORDER OF A REACTIONORDER OF A REACTIONFACTORS EFFECTING FACTORS EFFECTING

DECOMPOSITIONDECOMPOSITIONACCELERATED STABILITY STUDYACCELERATED STABILITY STUDYCONCLUSIONCONCLUSION

INTRODUCTIONINTRODUCTION

• The application of certain The application of certain physicochemical principles in the physicochemical principles in the performance of stability studies has performance of stability studies has proved to be of considerable proved to be of considerable advantage in the development of advantage in the development of stable dosage forms.stable dosage forms.

CHEMICAL DECOMPOSITION CHEMICAL DECOMPOSITION DECOMPOSITION DECOMPOSITION

PATHWAYSPATHWAYS • HYDROLYSIS

• OXIDATION –REDUCTION

• RACEMIZATION

• PHOTODEGRADATION

• DECORBOXYLATION

HYDROLYSISHYDROLYSIS

• Many pharmaceuticals contain ester or amide group undergo hydrolysis in solution catalyzed by acid or base.

• Esters: Ex: aspirin, procaine, atropine,

methyl-p-amino benzoate etc • Amides: Ex:chloramphenicol,niacinamide,

barbiturates ,phenothiazines

• Rate eqn: d[ester]/dt = -k[ester][H+] or

• = -k[ester][OH-]

• d[ester]/dt = K[ester].

• Stability can be improved by

• PH: pH of optimum stability and buffer concentration is kept at minimum.

• Type of solvent: replacement of water with solvent of lower DEC decrease the rate of hydrolysis.

• Ex:non-aq.solvents:ethanol,glycols, glucose ,mannitol solutions.

• Complexation:influence the rate by

1) Steric hindrance: caffeine-benzocaine.

2) Polar effects: by altering the affinity of ester –C=0 ion for catalysis .

• Surfactants:anionic,cationic,non-ionic,surfactants stabilize the drugs.

• The association of benzocaine close to the anionic head group of surfactants made a definite barrier to approach of hydroxyl ion into the micelle and attack on ester linkage

• Modification of chemical structure:• Salts and esters: in some cases decreasing the

solubility by forming salts and esters .Ex:acylsalicylates.

OXIDATION-REDUCTIONOXIDATION-REDUCTION

• Eg: steroids, vitamins, antibiotics and Eg: steroids, vitamins, antibiotics and epinephrine undergo oxidative epinephrine undergo oxidative degradation.degradation.

• Auto-oxidation: reaction of any material Auto-oxidation: reaction of any material with molecular oxygen. It is a free radical with molecular oxygen. It is a free radical chain process.chain process.

• Auto-oxidation of organic substance RH by Auto-oxidation of organic substance RH by free radical chain process.free radical chain process.

Initiation:Initiation: RH RH --------------- R* + (H*)--------------- R* + (H*) Propagation:Propagation: R* + OR* + O2 2 ----------- R O----------- R O22

R OR O2 2 + RH -------- ROOH +R* + RH -------- ROOH +R* hydroperoxide decomposition:hydroperoxide decomposition: ROOH ----------- RO* + *OHROOH ----------- RO* + *OH Termination:Termination:RORO22* + X------------ inactive products* + X------------ inactive products

RORO2 2 + RO + RO22 ----------- inactive products ----------- inactive products X = free radical inhibitor(sod.metabisulfite, thiourea, X = free radical inhibitor(sod.metabisulfite, thiourea,

cystiene HCl)cystiene HCl)

STABILITY CAN BE IMPROVED BYSTABILITY CAN BE IMPROVED BY

• Antioxidants: 1) act by preferential oxidation due to lower OP than the drug Ex:water soluble anti oxidants : sodium sulfite ascorbic acid sodium bisulfite isoascorbic acid sodium meta bisulfite thio glycerol sodium thio sulfate thioglycollic acid sodium fomaldehyde sulfoxylate cysteineHCL

• Act as chain inhibitors of free radicals by providing an electron and receiving the excess energy possessed by the activated molecule.

Ex: oil soluble antioxidants:

ascorbyl palmitate, hydroquinone

BHA BHT

propyl gallate, α-tocopherol,

Nordihydroguaiareticacid. Lecithin

PH:Nernst equation: oxidation potential

• Chelating agents:

complex with heavy metal ionscomplex with heavy metal ions

Ex: EDTA derivatives, dihydroxy ethyl glycine, Ex: EDTA derivatives, dihydroxy ethyl glycine, citric acid, tartaric acid,gluconic acid. citric acid, tartaric acid,gluconic acid.

• Solvents:Solvents: solvents other than water may have solvents other than water may have a catalyzing effect on oxidation reactions. a catalyzing effect on oxidation reactions.

eg:- aldehydes, ether, ketones.eg:- aldehydes, ether, ketones.

..

PHOTODEGRADETATION PHOTODEGRADETATION

• Nifedipine, nitroprusside,riboflavin,phenothiazines

• U.V illumination cause oxidation (photo oxidation) & scission (photolysis) of covalent bonds.

• The photo degradation of chlorpromazine through a semi quinoline free radical intermidiate follow zero order kinetics

Alcoholic solutions of hydrocortisone ,predinisolone Alcoholic solutions of hydrocortisone ,predinisolone & methy prednisolone degrade by first order & methy prednisolone degrade by first order kinetics . Light sensitive formulations can be kinetics . Light sensitive formulations can be protected by coloured glass containers Ex; yellow-protected by coloured glass containers Ex; yellow-green glass protects from U.V region while amber green glass protects from U.V region while amber confers protection from U.V.but little from I.R.confers protection from U.V.but little from I.R.

RACEMIZATION:process of changing from an RACEMIZATION:process of changing from an optically active compound into a racemic optically active compound into a racemic compound.compound.

it follows first order kinetics and depends on it follows first order kinetics and depends on temperature,solvent, presence or absence of light .temperature,solvent, presence or absence of light .

• Racemization appears to be depend on the functional group bound to asymmetric carbon atom aromatic group tends to accelerate the process.

• DECARBOXYLATION: some drugs undergo decomposition by decarboxylation.

• It follows first order kinetics highly ph dependent and catalyzed by H+ ions.

KINETIC PRINCIPLESKINETIC PRINCIPLES• A chemical reaction is the result of collision of

sufficient energy and of proper orientation.

Rate of reaction = collision frequency x energy factor x probability factor.

• Rate of reaction is the velocity with which reactant (s) undergoes a chemical change.

• Order of reaction is the manner in which the rate of reaction varies with the concentration of the reactants.

• consider the reaction,• aA + bB products

• According to law of mass action,• Rate = K[A]a[B]b K = rate constant .

ZERO ORDER REACTION• The reaction rate is the independent of the

concentration of the reacting substances.• -dA/dt =Ko• Example:.the loss in color of a liquid multisulfa Example:.the loss in color of a liquid multisulfa

preparation (as measured by decrease of absorbance preparation (as measured by decrease of absorbance at 500nm) followed a zero order reaction rate.at 500nm) followed a zero order reaction rate.

• Example: 2NH3(g) 3H2(g)+N2(g)Example: 2NH3(g) 3H2(g)+N2(g)• Pseudo or apparent order:Pseudo or apparent order: it describes a situation it describes a situation

whereon of the reactants is present in large excess or whereon of the reactants is present in large excess or doesn’t affect the overall reaction and can be held doesn’t affect the overall reaction and can be held constant . constant .

• Ex: suspensions,as the drug decomposes in solution more drug is released from the suspended particles so that the reaction remains constant.

• -dA/dt = kA -dA/dt =KoFIRST ORDER REACTION:The reaction rate depends on the first power of

concentration of a single reactant -dC/dt = kC

Ex:2H2O2(L) 2H2O(L)+ O2(g)PSEUDOFIRST ORDER REACTION: Ex: base catalysed ester hydrolysis. -d (ester)/dt = K [ester] [OH-] -d (ester)/dt = Ko [ester] Ex: cefatoxime sodium,

SECOND ORDER REACTION:SECOND ORDER REACTION: A + B products A + B products

-dA/dt = -dB/dt = K[A][B] -dA/dt = -dB/dt = K[A][B]2NO2NO22(g) 2NO(g) + O(g) 2NO(g) + O22(g)(g)

Order of reaction

Rate equation Half life Shelf life

0 At= Ao-Kt Ao/2Ko 0.1Ao/Ko

1 Kt =2.303logCo/C

0.693/K 0.104/K or 0.152t1/2

2 x/a(a-x) = kt 1/aK 1/9aK

DETERMINATION OF ORDER OF A REACTION

1)SUBSTITUTION METHOD: calculate k value with formula

2)GRAPHIC METHOD: C vs. time, logC vs. time, 1/C vs. time

3)HALF LIFE METHOD:

T1/2α 1/an-1

FACTORS AFFECTING DECOMPOSITIONFACTORS AFFECTING DECOMPOSITION• 1)PH: The magnitude of rate of hydrolytic reactions The magnitude of rate of hydrolytic reactions

catalyzed by hydrogen and hydroxyl ions can catalyzed by hydrogen and hydroxyl ions can vary considerably with pH.hydrogen ion catalysis vary considerably with pH.hydrogen ion catalysis predominates at lower pH range,where as predominates at lower pH range,where as hydroxyl ion catalysis predominates at higher pH hydroxyl ion catalysis predominates at higher pH rangerange

• At the intermediate pH range, rate can be At the intermediate pH range, rate can be independent of pH or catalyzed by both independent of pH or catalyzed by both hydrogen and hydroxyl ions. hydrogen and hydroxyl ions.

• Rate constants at this pH are less than those at Rate constants at this pH are less than those at higher or lower pH values. higher or lower pH values.

the pH of optimum stability can determined the pH of optimum stability can determined by plotting of the logk vs. pH.by plotting of the logk vs. pH.

• 2)TEMPERATURE: the most satisfactory method for expressing the temperature on reaction rate is given by Arrhenius,

• K= Ae-Ea/RT,K= Ae-Ea/RT, K = specific reaction constant ,K = specific reaction constant ,

A =frequency factor .A =frequency factor . Ea= energy of activation,Ea= energy of activation, R = gas constant ,R = gas constant , T = absolute temperature, T = absolute temperature, log K = logA –Ea/2.303RTlog K = logA –Ea/2.303RT

logK vs.logK vs. 1/T yields a straight line 1/T yields a straight line

• DIELECTRIC CONSTANT:

lnK = lnkε=∞ - NZAZBe2

RT r ε

kε=∞ = rate constant in a medium of a infinite DEC N = Avogadro’s number, ZA & ZB = charges on the two ions e = unit of electric charge

r = distance between ions in the activated complex ε = DEC of a solution If the reactants are opposite sign slope is +ve so increase in

DEC , decrease in rate constant like sign slope is –ve increase in DEC increase in rate

constant

• IONIC STRENGTH: influence of ionic strength on reaction rate is given by

Logk=logko+1.02 ZLogk=logko+1.02 ZAA Z ZBBõõ

ZZA A and Zand ZBB are the charges carried by the reacting are the charges carried by the reacting

species in solution, µ, the ionic strength, Ko (Rate species in solution, µ, the ionic strength, Ko (Rate const at infinite dilution).const at infinite dilution).

IONIC STRENGTH:

drug Catalyzed by Ionic strength

Rate

+vely charged

H+ Increases (with Nacl)

Increases

+vely charged

OH- Increases decreases

Neutral - changes No change

ACCELERATED STABILITY STUDIES

Free and Blythe have suggested a method :

A graph of log concentration of drug remaining vs. time

at different temperatures.

• Log time to 90% vs. 1/t extend the line to meet 25ºC gives the shelf life of product

• Log time to 90% vs. 1/T,

• It gives the shelf life of product.

LIMITATIONS: testing methods based on Arrhenius law are valid only when

breakdown is a thermal phenomenon, Eact about 10 -30 KCal/mol.• If the reaction rate is determined by diffusion or

photochemical reaction or if decomposed due to freezing, contamination by microorganisms…..

• Not used for products containing suspending agents like methyl cellulose undergo coagulation .proteins – denaturation ,melting of ointments and suppositories.

• Where accelerated stability studies are not applicable extended aging tests must be employed

under various conditions to obtain the desired information.

REFERENCES

• The Theory and Practice of Industrial Pharmacy, by Leon Lachmen, third Edition, P: 760-775.

• Text book of Physical Pharmacy by Alfred Martin, Fourth Edition, P: 284-288, 295 – 302.

• Stability of Drugs and Dosage forms by Valentino J.Stella.

• Drug stability by cartensen.• Remington’s pharmaceutical sciences