Drug Stability Flashcards
What are the 3 types of Degradation?
- Chemical
- Physical
- Microbiological
What is chemical degradation?
=> inaccuracy in dosing & possibly therapeutic failure
What is physical degradation?
=> decrease bioavail. => decrease therapeutic efficacy
- can occur through physiochemical changes &/or excipients such as PRODUCTION OF POLYMORPHS
What is microbiological degradation?
microbial growth & ability of the product to remain sterile/resistant to growth
What are the 4 types of Chemical degradation?
- Hydrolysis - decomp. of drug through rxn w/ water/solvent; as it acts as a nuc & attacks electrophilic sites
- Oxidation - strongly influenced by light, metal ions, O2 & oxidizing agents
- Photolysis - sunlight &/or room light may cause degradation through an oxidative process w/ light providing energy (a photon) for the initiation & propagation steps
- Miscellaneous - chemical rxns such as: hydration, additions, decarboxylation & Schiff’s base formulation can occur
Many compounds are more resistant to ox @ _____ pH
LOWER
Greater the # of C to O bonds, the ____ oxidized the molecule
MORE
When electromagnetic radiation absorbed by a molecule, 1 of the following events may occur:
- molecule decomposes w/ release of free radical
- energy retained until it can be used chemically or transferred to another molecule
- energy converted to heat & NO rxn occurs
- absorbing molecules emit light of diff wavelengths & NO rxn occurs
What are the 4 types of Physical degradation?
- Polymorphism - differ in internal crystal structure & therefore crystal energies differ which results in solubility differences
- Vapourization - ~ drugs have HIGH VP that ~ of the active is lost through vapourization
- Aging - where changes occur in the disintegration/dissolution properties
- Adsorption - drug loss to packaged materials
Shelf-life (t90):
time @ which the initial [ ] of active in the product has DECREASED by 10%
Half-life (t50):
time @ which the initial [ ] has DECREASED by 50%
Order of a rxn determines the _____ of [ ]-time profile; Rate constant determines its _____
SHAPE
SLOPE
Rate of rxn is proportional to ______________
number of collisions
Number of collisions is proportional to the ____________
product of the [ ] of the reacting species
What does 1st order mean?
drug loss is DIRECTLY proportional to the [ ] remaining w/ respect to time
What does 0 order mean?
the loss of drug is INdependent of [ ] & constant w/ respect to time
What are the factors affecting rxn rates?
- Temp
- Catalysis
- pH
- Solvent effects
- Solubility effects
a. hydrolysis
b. oxidation
What are the solvent effects generally?
- INCREASE in solvent polarity accelerates the rates where CHARGE develops in the activated complex
- DECREASES the rates where there is LESS charge in the activated complex compared to the starting material
- Change in solvent polarity will have little or no effect on the rates where there is little difference in charge b/t the reactants & the activated complex
What is a solubility effect?
drug in solution may undergo apparent 1st order rxn, but when formulated as a suspension, it decomposes through apparent 0-order kinetics
Solubility effects: Hydrolysis
1) Exclude water from product
- drug must be in solution for hydrolysis to occur, so exclusion of water will slow the rate of decomposition
2) Control pH
3) Control temp
- storing @ reduced temp may INCREASE product stability, but freezing should NOT be used
4) Use of cosolvents
5) Complex formation
6) Supply drug in solid form
- form. as a suspension may be useful since drug will probs degrade through apparent 0-order kinetics
Solubility effects: Oxidation
1) Protect from light
2) Exclusion of O2
3) Control of pH
4) Addition of antioxidants (are more easily oxidized than the product)
What is real time stability testing?
to provide evidence on how the quality of a product, in its marketing packaging, varies w/ time under the influence of factors, such as temp, humidity & light
What is the Q10 method of shelf-life estimation?
est. temp effects on rxn rates
Q10 is factor by which the rate constant INCREASES for a 10 degree C temp. INCREASE
Reasonable estimates can often be made using the value of 3
