Stability

1
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

2
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

3
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

4
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

5
Kinetics

• rates and orders of reactions
• use
• more stable dosage forms
• storage conditions
• prediction of shelf life
• factors
• concentration
• temperature
• light
• catalysts

6
Factors governing stability

• Liquids
• pH
• temperature
• ionic strength
• solvent
• oxygen
• Solids
• excipients

7
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 DGo
• forms a complex with reactant
• decomposes to form product catalyst

8
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-

9
Hydrolysis of Ester

• acid-catalyzed degradation
• ester S
• water W
• product P
• base-catalyzed degradation

10
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.

11
Solvent catalysis

• indicated by minimum region of k versus pH plot
• can occur along with both acid and base catalyzed
  degradation

12
General Acid-Base Catalysis

• catalysis in buffered solution by other than H
  or OH-
• kobs vs pH diagram deviates from expected
  behavior
• streptozotocin in phosphate buffer

13
Effect of T

• Arrhenius

14
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.

15
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, m
• influences rate constant

16
Solid Dosage Forms

• Stability concerns
• moisture
• hygroscopic excipients
• excipient catalyzed reactions
• ex. Mg stearate lubricant

17
Drug Stabilization

• primarily hydrolysis
• strategies
• optimum pH, buffer, solvent
• refrigeration
• complexation agent
• dosage form
• emulsion, suspensions
• oxidation
• antioxidants
• undergo oxidation faster
• sodium bisulfite, ascorbic acid
• ascorbyl palmitate, butylated hydroxytoluene
  (BHT), vitamin E

18
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

first order
2nd order
zero order
19
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?