B. Amsden CHEE 440

Stability

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

B. Amsden CHEE 440

Degradation Mechanisms

Hydrolysis cleavage of bonds by action of water esters

• procaine, atropine, aspirin amides

• chloramphenicol, penicillin, cephalosporins

Oxidation molecule gains O or loses H susceptible compounds

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

examples• epinephrine, vitamin A, ascorbic acid

B. Amsden CHEE 440

Degradation Mechanisms

photo-degradation light energy provides energy of activation reaction rate is independent of T photo-oxidation

• catalyzed by light• nifedipine, colchicine, chlorpromazine, riboflavin

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

B. Amsden CHEE 440

Degradation 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

B. Amsden CHEE 440

Factors governing stability

Liquids pH temperature ionic strength solvent oxygen

Solids excipients

B. Amsden CHEE 440

Effect Of pH

Catalyst substance that influences rate of reaction but is not changed

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

forms a complex with reactant• decomposes to form product + catalyst

B. Amsden CHEE 440

Acid-Base Catalysis

accelerated decomposition in presence of acid or base

often buffered therefore catalyzed

specific acid-base catalysis

rate law contains [H3O+] or [OH-]

B. Amsden CHEE 440

Hydrolysis of Ester

acid-catalyzed degradation ester = S water = W product = P

base-catalyzed degradation

S +H+ ⇔ SH+

SH+ +W⇔kP

dP

dt=kobsS[ ]

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kobs = kH+ H+

[ ]

S +OH−→k2P

dP

dt=kobsS[ ]

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kobs = kOH− OH−

[ ]

B. Amsden CHEE 440

Example

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.

B. Amsden CHEE 440

Solvent catalysis

indicated by minimum region of k versus pH plot

can occur along with both acid and base catalyzed degradation

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dP

dt= kH2O + k

H+ H+[ ] + k

OH− OH−[ ]( ) S[ ]

B. Amsden CHEE 440

General Acid-Base Catalysis

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

kobs vs pH diagram deviates from expected behavior

ex. streptozotocin in phosphate buffer

B. Amsden CHEE 440

Effect of T

Arrhenius k =Aexp−E aRT

⎛ ⎝

⎞ ⎠

B. Amsden CHEE 440

Example

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.

B. Amsden CHEE 440

Other Influences

Solvent 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

Ionic strength, influences rate constant

μ=12

mizi2∑

logk =logko+2AzAzB μ

B. Amsden CHEE 440

Solid Dosage Forms

Stability concerns moisture hygroscopic excipients excipient catalyzed reactions

• ex. Mg stearate lubricant

B. Amsden CHEE 440

Drug Stabilization

hydrolysis strategies

• optimum pH, buffer, solvent• refrigeration• complexation agent• dosage form

• emulsion, suspensions

oxidation add antioxidants

• sodium bisulfite, ascorbic acid• ascorbyl palmitate, butylated hydroxytoluene (BHT),

vitamin E

B. Amsden CHEE 440

Shelf-Life

effective period of storage and use

t90

time required to degrade 10% of the drug 90% drug still active determined by reaction kinetics

t 90 =−ln 0.9( )k1

t 90 =A0[ ]

10k0t 90 =

19 A0[ ]k2

first order 2nd orderzero order

B. Amsden CHEE 440

Example

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). What is its shelf life?