Chemical kinetics and stability of dosage forms Flashcards
Common mechanisms of degradation
Hydrolysis
oxidation
isomerization
Photochemical degradation
Polymerization
Hydrolysis
The most common pathway for drug breakdown
Susceptible drugs include aspirin, procaine (ester), penicillins (amide, lactam) and benzodiazepines (lactam)
Can be H+ or OH- catalyzed (optimize formulation to minimize)
May be be possible to modify drug structure to prevent hydrolysis
oxidation
Commonly via a peroxy radical (ROO*) but there are other mechanisms
Susceptible drugs include steroids & sterols and polyene antibiotics (C=C), ethers and sulphur groups also prone
Can be catalyzed by action of UV, heat or trace metals
Use antioxidants
Isomerization
Racemization, where an enantiomerically pure compound becomes a racemic mixture
photochemical degradation
Amber glass to block UV, coat tablets with UV-absorbing polymer
polymerization
Can occur at high concentration
routes of degration
direct
dynamic equilibrium
competitive
sequential
order of reaction
Order of reaction is the sum of the powers
first order kinetics
ln[A]t= ln[A]0 -kt
c= ln[A]0
slope= -k
y= [A]
x=time
half-life
t1/2 =0.693/k
shelf life
ln(1/percentage as decimal)/ k
t95%= 0.0513/k
is independent of initial conc
Ratio of t½ to t95%
t1/2 / t95%
find values u have to take the ln
Shelf life
The shelf life of a medicine is the time that a specific drug characteristic remains within a particular specification (“acceptance criteria”) after manufacture when stored according to the label.
Can be based on the amount of drug remaining or the accumulation of a degradation product.
Definitions vary and can depend on a number of factors.
Can be estimated mathematically, by extrapolation, but requires analytical confirmation.
For these lectures we will define shelf life as the time that the drug remains at or above 95% of the label dose (t95%).
Zero Order Kinetics
ln[A]t= ln[A]0 -kt
Rate is independent of concentration of reacting species
[A]solution is constant
Thus, the rate is constant
slope = -k
t1/2 = [A]0/2k
t95% = [A]0/20k
shelf - life is dependent on initial concentration
Once the solid particles in suspension are fully solubilized by the solution, the degradation will no longer follow zero order!
Second Order Kinetics
The rates of bimolecular reactions, which occur when two molecules come together to form the product, are commonly described by the 2nd order equation.
Two possibilities exist:
- Rate is proportional to the product of two equal concentrations, either involving a single reactant or two different reactants:
- Rate is proportional to two different concentrations:
Second Order Kinetics, [A] = [B] or 2[A]
1/[A]t =1/[A]0+kt
slope= k
t1/2= 1/[A]0 k
t95= 1/19 [A]0 k
Shelf life is dependent on initial concentration
Second Order Kinetics – Type 2: [A] ≠ [B]
different
Methods of Determining Reaction Order
substitution method
shelf life method
Based on the relationship between [A]0, t95% and reaction order:
For zero order, increasing [A]0 increases t95%
For first order, [A]0 and t95% are independent
For second order, increasing [A]0 decreases t95%
graphical method
in ln [A]
zero-
first
second
