Drug Stability, pH Dependence, Shelf Life Flashcards
What happens at higher T?
How to we increase shelf life?
Higher temperature—> higher higher reaction rate
Lower temperature—> lowers reaction rate—> increase shelf life
What is the rule of thumb changes in rxn rate?
What produces 2, 3,6 fold decrease?
10c decrease in temp can reduce reactivity (increase shelf life) by 2/3 times or even 6 times in rare cases
0.56–>2 (10k cal/mol decrease)
0.31–> 3 (20k)
0.17–> 6 fold decrease (30k)
How do we determine shelf life?
For products with 2+ shelf life—> impractical to test the formulations at different temperatures to see which has the longer stability
What is the procedure for determing shelf life? 1step
Step 2?
Step 3?
Determined bufferless kobs at several accelerated temperatures at specified pHs
Plot ln kobs vs. 1/T & extrapolate to desired shelf life temp to obtain kextrap
Calculate shelf life
How does pH influence shelf life?
H and OH at extremes ph
Buffering species, which may also catalyze the rxn
Multiple reaction sites
Different forms of the drug ( protonated or deprotonated)
How to construct a pH rate profile?
1: Determine rate constant as a function of buffer conc
2: determination of bufferless rate constant by extrapolating Kobs to zero buffer conc
3: plot log kabs vs ph
What are reactions of carboxyl compounds with water?
Acyl group transfers
Carboxyl compounds— carboxylic acid, ester, amide, thiol ester—may not be stable, can react with amines
What is base catalysis of ester functional group?
Finish
O is EN —> OH- will attack acyl carbon—> forming tetrahedral intermediate
