shelf llife Flashcards
what is gibbs free energy equation?
ΔG = ΔH – T ΔS
what does gibbs free energy reaction tell us?
it tells us is a reaction favorable, not how fast a reaction takes place
what does the Arrhenius model do?
it relates reaction rate to temperature
k = Ae>-Ea/RT or ln(k) = ln(A) – Ea/RT (y=mx+c)
what is the advantage of using the arrhenius model?
Once k is known at various temperatures it can be estimated at (any) temperature–Hence, based on empirical data
what does the transition state theory:Eyring Equation compliment?
TST complements collision theory
why is the eyring equation good/ better than the arrhenius model?
Allows determination of both enthalpic and entropic values – useful in determining mechanisms!
what happens in a real time study for shelf life?
Recommended storage conditions tested
•Time taken to reach minimum permitted level of active
•Time taken to reach maximum permitted level of degradation product
•Applies only to storage conditions used in the trial
what is a disadvantage of real time study?
If medicine is stable then trial is very time consuming–Could take up to two years to collect data
what is mean kinetic temperature?
- Alternative to using mean temp
single derived temperature which, if maintained over a defined period, would afford the same thermal challenge to a product as would have been experienced over a range of higher and lower temperatures over the same time period.
is the mean kinetic temperature higher or lower than the simple mean value?
mean kinetic temperature is higher
what does the mean kinetic temperature accommodate?
- Accommodates daily and seasonal changes
* Can be used to check changes in storage conditions
what does accellerated stability require?
Requires a factor which changes degradation rate reproducibly–Temperature–Light intensity–pH
•Ideally should be use a mathematical model relating factor to degradation rate (Q rules).
how do you select temperatures when preforming accellerated stability?
Select three or four high temperature points–High enough to significantly affect the rate–Not so high as to destroy the integrity of the medicine–May use one low temperature point to establish validity of the model (e.g. 5 °C)
how do you measure the content of active remaining?
–Must use a ‘stability-indicating’ assay; probably chromatographic
–May measure degradation product simultaneously
what are the ways in which ramipril can degrade?
n-oxide
amide hydrolysis
ester hydrolysis
benzyl radical -hydroperoxide
what happens if the rate constant doubles?
then the shelf life halves, whatever the reaction order
what does a straight line on a graph indicate?
first order reactions
is it possible to estimate the shelf life at another temperature given the temperature of a specific one?
yes
when in doubt is it better to over/understimate the shelf life?
underestimate
what are the limitations of arrheneus?
Change in reaction path Activation energy is not completely temperature independent Protein and peptide drugs denature phase changes loss of oxygen loss of moisture
what are the regulatory submissions? (normal tests)
Assay methods
Stability indicating- distinguish and quantify
Usually chromatographic (HPLC)
through valudation
international Council on Harmonization (ICH) guidelines
Drug substance
Expected storage (long term) and accelerated conditions
Forced degradation
what is the minimum number of batches?
3
what testing on excipients would be preformed?
–Antimicrobial–pH–Physical change (e.g. sedimentation)–Microbiological integrity
does change require retesting?
yes - any change requires retesting
