CHEE 440 1

StabilityStability

the extent to which a product retains, within specified limits, and throughout its period of storage and use, the same properties and characteristics it possessed when manufactured

types chemical physical microbiologic therapeutic toxicologic

CHEE 440 2

Degradation MechanismsDegradation Mechanisms

Hydrolysis cleavage of bonds by action of water esters

» procaine, atropine, aspirin amides

» chloramphenicol, penicillin, cephalosporins

CHEE 440 3

Degradation MechanismsDegradation Mechanisms

Oxidation molecule gains O or loses H susceptible compounds

» phenols, aromatic amines, aldehydes, ethers, unsaturated aliphatic compounds

examples

» epinephrine, vitamin A, ascorbic acid

CHEE 440 4

Degradation MechanismsDegradation Mechanisms

photodegradation light energy provides energy of

activation reaction rate is independent of T photo-oxidation

» catalyzed by light

» nifedipine, colchicine, chlorpromazine, riboflavin

CHEE 440 5

Degradation MechanismsDegradation Mechanisms

isomerisation conversion of a drug into its optical

isomer enantiomers often have significantly

different ADME and pharmacological action

often catalyzed by acid or a base ex. tetracycline, pilocarpine,

cephalosporin esters

CHEE 440 6

Degradation MechanismsDegradation Mechanisms

Interactions between formulation compounds buffers

» general acid-base catalysts

» formation of amides benzocaine and citric acid

accelerated photodecomposition

» riboflavin in presence of nonionic or anionic surfactant

CHEE 440 7

KINETICSKINETICS

rates and orders of reactions use

more stable dosage forms» storage conditions

prediction of shelf life factors

concentration temperature light catalysts

CHEE 440 8

Factors governing Factors governing stabilitystability

Liquids pH temperature ionic strength solvent oxygen

Solids excipients

CHEE 440 9

EFFECT OF PHEFFECT OF PH

Catalyst substance that influences rate of

reaction but is not changed chemically either accelerates or inhibits does not change position of equilibrium no change in Go

form a complex with reactant decomposes to form product + catalyst

CHEE 440 10

Acid-Base CatalysisAcid-Base Catalysis

accelerated decomposition in presence of acid or base

often buffered therefore catalyzed

specific acid-base catalysis rate law contains [H3O+] or [OH-]

CHEE 440 11

Hydrolysis of EsterHydrolysis of Ester

in acidic solution ester = S water = W product = P

S +H+ ⇔ SH+

SH+ +W⇔kP

dP

dt=kobsS[ ]

kobs =k1 H+

[ ]

CHEE 440 12

Hydrolysis of EsterHydrolysis of Ester

base-catalyzed degradation

S +OH−→k2P

dP

dt=kobsS[ ]

kobs =k2 OH−

[ ]

CHEE 440 13

ExampleExample

Drug X degrades by a base-catalyzed process in a buffer of pH 9 at room T. If the initial concentration of X was 0.1 M and after 4 days there was 0.099 M of X present, determine k2 for this reaction.

CHEE 440 14

Solvent catalysisSolvent catalysis

indicated by minimum region of k versus pH plot

can occur along with both acid and base catalyzed degradation

dP

dt= ko + k1 H

+[ ] + k2 OH

−[ ]( ) S[ ]

log

k obs

pH

CHEE 440 15

General Acid-Base General Acid-Base CatalysisCatalysis

catalysis in buffered solution by other than H+ or OH-

kobs vs pH diagram deviates from expected behavior streptozotocin in phosphate buffer

CHEE 440 16

Effect of TEffect of T

any change in conditions produces different k Arrhenius

A = Arrhenius factor

» frequency of collisions Ea = activation energy

» minimum energy required per collision

used in accelerated stability testing

k =Aexp−E a

RT ⎛ ⎝

⎞ ⎠

CHEE 440 17

ExampleExample

The rate constant for the decomposition of expensinin at 120 °C is 1.173 hr-1 and at 140 °C is 4.86 hr-1. Calculate the activation energy and the Arrhenius factor for this reaction.

CHEE 440 18

Effect of SolventEffect of Solvent

affects rate constant polar solvents increase the rate of

reaction where the products are more polar than the reactants

nonpolar solvents increase the rate of reaction where the products are more nonpolar than the reactants

CHEE 440 19

Effect of Ionic StrengthEffect of Ionic Strength

ionic strength,

influences rate constant

μ=12

mizi2∑

logk =logko+2AzAzB μ

CHEE 440 20

Solid Dosage FormsSolid Dosage Forms

Stability concerns moisture hygroscopic excipients excipient catalyzed reactions

» ex. Mg stearate lubricant

CHEE 440 21

Drug StabilizationDrug Stabilization

primarily hydrolysis strategies

» optimum pH, buffer, solvent

» refrigeration

» complexation agent

» dosage form micelles, suspensions

oxidation antioxidants

» undergo oxidation faster sodium bisulfite, ascorbic acid ascorbyl palmitate, butylated

hydroxytoluene (BHT), vitamin E

CHEE 440 22

Shelf-LifeShelf-Life

effective period of storage and use

t90

time required to degrade 10% of the drug

90% drug still active determined by reaction kinetics

CHEE 440 23

tt9090

zero-order

first order

second order

t 90 =−ln 0.9( )

k1

t 90 =A0[ ]10k0

t 90 =1

9 A0[ ]k2

CHEE 440 24

ExampleExample

An ophthalmic solution has a mydriatic drug present at a 5 mg/ml concentration. The drug degrades by first order kinetics (k1 = 0.0005/day). how long will it take for the drug to degrade to 90% of its original concentration?